Arjun Muralidharan, PhD, is a research fellow in the Charles Perkins Centre at The University of Sydney, Australia. He completed his PhD in the laboratory of Maree Smith at the University of Queensland in 2013 and recently returned to Australia after being awarded the Ronald Melzack Fellowship in Pain Research from the Alan Edwards Centre for Research on Pain, McGill University, where he completed a postdoctoral fellowship in the Pain Genetics Laboratory of Jeffrey Mogil. Muralidharan recently won the Australian Pain Society’s Rising Star Award for 2019, which showcases up-and-coming pain researchers in Australia.
Muralidharan sat down with Lincoln Tracy, a research fellow from Monash University, Australia, at the 2019 Australian Pain Society 39th Annual Scientific Meeting, which took place April 7-10, 2019, on the Gold Coast, Australia. Muralidharan discussed his journey to pain research, what winning the Rising Star Award means to him, and his love of cricket. Below is an edited transcript of their conversation.
What got you interested in science?
I’ve always been an ardent lover of science. It’s a subject that captures so many of life’s issues. It makes sense of, and creates order in, what otherwise might seem chaotic. I can’t imagine something more empowering than that.
How did you end up in pain research?
I credit my motivation for research in pain to two people: Professor Yogeeswari Perumal from the Birla Institute of Technology and Science in India, and Dr. Vaigundaragavendran Jegadeesan, a PhD student of hers from about 10 years ago. When I was a second-year undergraduate, I approached them for projects, as they had really well-established chronic pain models in their lab. When I started working with them, I was really naïve to think, Why are people trying to cure chronic pain when we have paracetamol? At that stage I didn’t know that chronic pain was such an intractable condition.
From there, I was trained in various nociceptive and chronic neuropathic pain models, and have been researching peripheral neuropathies ever since. I did work on depression and schizophrenia for a short while but ultimately chose pain research, as I spent three years of my undergraduate degree and my honors thesis on various projects. From there, the support from my three inspirational mentors—Maree Smith, Jeffrey Mogil, and Greg Neely—has kept me on this path.
What does winning the Australian Pain Society Rising Star Award mean to you?
Personally, it’s awesome. This award is validation that I am on the right path, and that what I am most passionate about works. It’s a real confidence boost for my career in pain research. Professionally, the award is a sign of credibility as a scientist and recognition within the pain community. But recognition aside, I think just applying for awards, or seeking to be nominated for an award, brings a multitude of professional benefits. It takes a lot of work to put your CV out there, and as part of that process, you identify the shortcomings in it. While winning the award is great, it also gave me an opportunity to undergo a personal and professional self-assessment.
What kinds of studies are you working on at the moment?
I’m still pursuing the line of research I undertook during my fellowship in the Pain Genetics Laboratory of Jeffrey Mogil. We have established an interaction between chronic pain and aging pathways, and now I’m trying to illustrate the molecular mechanisms that underpin this interaction.
In addition to pain neurobiology, I am also expanding my line of research into other areas of pain management. With Greg Neely’s lab at the University of Sydney, we are currently working on developing an allogeneic stem cell-based analgesic therapy for the treatment of chronic neuropathic pain. I’m really excited about this project, as the availability of allogeneic therapies such as these can drastically increase the number of chronic pain patients we are able to help.
We are also working on rapidly actionable dietary interventions for the treatment of chronic pain. Researchers at the Charles Perkins Centre at the University of Sydney have shown that you can either prolong or reduce the lifespan of animals by modulating the ratio of proteins to carbohydrates in their diet. Since my previous research at Jeffrey Mogil’s lab has shown that long-term chronic pain can accelerate cellular aging and increase the likelihood of premature death, we are currently investigating whether these pro-longevity dietary interventions have an effect on cellular aging and pain in our animal models of chronic pain.
What are some of the challenges associated with undertaking research into genetics and pain?
Intra-individual variability in pain sensitivity and analgesia, rodent heritability, familial aggregation, and twin studies have shown that between 40 and 60 percent of pain perception involves a genetic component. But the big question is, How many genes are actually involved? Two decades ago we were all thinking that it’s going to be just a handful of genes—that we just had to figure out which ones they are and then it’s all done. We know now that there are 22,000 genes in the human genome. Given the complexity of chronic pain, my guess would be that perhaps up to 5,000 genes are involved in it, and we have figured out maybe 100 of these.
But even if we get all the funding in the world and we find all the possible genes involved in pain, what are we actually going to do with them? Chances are that these genes are going to be involved in most cellular pathways. However, genetic techniques are becoming powerful—a so maybe we will get a handle on this thing. But this is just the challenge in the protein coding region—which accounts for only about 2 percent of the genome. The remainder of the genome is abundantly transcribed to long and short noncoding RNAs (ncRNAs), and recent research is slowly starting to highlight the involvement of ncRNAs in pain genetics as well.
What has been the most interesting study you have been involved with over your career?
During my time in Maree Smith’s lab, we were able to implicate signaling of the augmented angiotensin II/angiotensin II type 2 receptor (AT2R) in the pathobiology of chronic pain. In cultured neuronal cells, angiotensin II/AT2R-induced neurite outgrowth has been shown to be driven by persistent MAP kinase activation. Given the known role of MAP kinases in sensory neuron hyperexcitability and neuropathic pain, we thought that angiotensin II/AT2R signaling may play a role in chronic pain. We found augmented levels of angiotensin II in the lumber dorsal root ganglion in both a chronic constriction injury neuropathic pain model and a prostate cancer bone pain model. However, administration of the AT2R antagonists EMA200 and EMA300—analogues of the clinically active EMA401—suppressed angiotensin II and MAP kinase activity, as well as a set of nerve growth factors. EMA401 has now shown significant analgesia in postherpetic neuralgia patients, so we hope that this will make it to the clinical setting after Phase 3 and Phase 4 studies.
What are some of the important things you try to teach the students who you work with?
The first thing I always say, regardless of what field you are going into, is choose a field that you are passionate about. The passion is what is going to motivate you to undertake research. It’s also important that you understand the problem in the clinical context first. Once you understand this, then you can mirror the same thing in animal models or through other basic research approaches.
Another really important thing that Maree Smith taught me is that research is not a sprint—it is a marathon. I’ve seen a lot of students who are highly motivated when they start their PhD and start off well. But toward the end of the PhD, they slow down when they need focus more than anything. Anyone can start a story and write different chapters, but tying all your chapters into a single representative story is the most important thing. Finally, and most importantly, Maree Smith taught me to never be selfish when it comes to authorship. Pain is too complex for one author, one discipline, or one profession alone.
Within the field of pain research, is there an influential paper that you think all researchers should read?
I would recommend a recent review article from Yezierski and Hansson that discussed the preclinical strategies used in inflammatory and neuropathic pain research. It’s a timely, scholarly, and comprehensive review that clearly discussed reasons underlying the failure of preclinical to clinical translation in pain research.
Prior to this review, one paper I always liked was Jeffrey Mogil’s paper highlighting the research gaps in preclinical animal models in pain research. This paper helped me to frame key aspects of my research story, in that many animal models of pain are studied over a short time frame in young animals. In addition, analgesic testing in these animal models occurs very soon after injury—one to two months post-surgery at most. It’s possible that analgesic drugs discovered using those methods may produce analgesia only in young humans who have recent injuries and may not do so in young humans with old injuries or in old humans with old or recent injuries. This paper highlighted this gap in pain research.
When you’re not doing research, what are you doing?
Coming from India, I love cricket. If it was not for science, I would have loved to go into professional cricket, but my parents would have never allowed me. They wanted me to have education, not a game, in my life. I also like trying out new recipes, although they almost never turn out the way that they should!
If you could have a dinner party with anyone from history, whom would you want at the table with you?
Definitely Jean-Baptiste Lamarck. In the early 19th century he proposed a theory about how species evolve as they age and give these traits to their offspring. Although his theories have since been disproven, his work helped guide Darwin to shape his own theories on evolution and heritability. Science is not always a story of overwhelming successes; it is also a story of overcoming failures and of hard work. So I actually acknowledge Lamarck’s work as a more important theory of evolution than Darwin’s.
Lincoln Tracy is a postdoctoral research fellow in the School of Public Health and Preventive Medicine at Monash University and a freelance writer from Melbourne, Australia. You can follow him on Twitter @lincolntracy.
Inflammatory and neuropathic pain from bench to bedside: What went wrong?
Yezierski RP, Hansson P
J Pain. 2018 Jun; 19(6):571-588.
New horizons: Dietary protein, ageing and the Okinawan ratio.
Le Couteur DG, Solon-Biet S, Wahl D, Cogger VC, Willcox BJ, Willcox CD, Raubenheimer D, Simpson SJ
Age Ageing. 2016 July; 45(4):443-7.
Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain: preclinical and clinical studies.
Smith MT, Anand P, Rice ASC
Pain. 2016 Feb; 157 Suppl 1:S33-41.
Analgesic efficacy and mode of action of a selective small molecule angiotensin II type 2 receptor antagonist in a rat model of prostate cancer-induced bone pain.
Muralidharan A, Wyse BD, Smith MT
Pain Med. 2014 Jan; 15(1):93-110.
A small molecule angiotensin II type 2 receptor (AT2 R) antagonist produces analgesia in a rat model of neuropathic pain by inhibition of p38 mitogen-activated protein kinase (MAPK) and p44/p42 MAPK activation in the dorsal root ganglia.
Smith MT, Woodruff TM, Wyse BD, Muralidharan A, Walther T
Pain Med. 2013 Oct; 14(10):1557-68.
Animal models of pain: progress and challenges.
Nat Rev Neurosci. 2009 Apr; 10(4):283-94.