APS2022: IASP Global Year Lecture: Complexity of Pain Underlies Importance of Impact and Translation

Prof Mark Hutchinson

The following is a summary from the 42nd Annual Scientific Meeting of the Australian Pain Society, which took place from April 10-13 in Hobart, Tasmania. Since 2019, the Meeting has featured a named plenary lecture on the International Association for the Study of Pain’s (IASP) Global Year Against Pain, an advocacy effort to raise awareness of pain. Professor Mark Hutchinson, Director of the ARC Centre of Excellence for Nanoscale BioPhotonics and Professor within the Adelaide Medical School at the University of Adelaide, had the privilege of delivering the IASP Global Year Named Lecture for 2022. His research explores the “other brain”—or the other immune-like cells within the brain and spinal cord—and has implicated these cells in the action of drugs of dependence and the negative side effects of pain treatments. Keeping in line with the Global Year theme of translating pain knowledge into practice, Hutchinson spoke about his experiences with the Centre for Nanoscale BioPhotonics in taking science from the benchtop to the boardroom to translate more impact, and how these learnings can be applied to pain.

Pain is a complex problem

Hutchinson started the lecture by focusing on the global issue of pain. Although pain may not necessarily have the headline-grabbing scenario of death as an endpoint like for heart disease, people can live with pain for many years. In fact, data from the most recent Global Burden of Disease study identified that conditions associated with, or driven entirely by, pain accounts for more than three quarters of the total years lived with disability on a global scale. This is an incredibly important issue. But according to Hutchinson, we don’t do a good enough job at communicating this.

Part of why we don’t communicate this well is because of how complicated pain is. Although Hutchinson agreed that a biopsychosocial model is a great way to conceptualise pain and explain why it is important, things very quickly become complicated when you try and break down what we mean by a biopsychosocial pain system. Such a system operates on a vast scale of length: single molecules and cell membranes nanometres apart through to social interactions occurring on the metre scale. And this doesn’t even consider the complexities of the time of biology, from milliseconds to years!

Nociception isn’t any less complicated

Pain is clearly a complicated process. But nociception isn’t any better, as Hutchinson went on to explain. He asked the audience to consider whether nociception is an analogue response (which focuses on how intense each cell responds to a stimulus, not how many cells are responding) or a digital response (where the focus is on the number of cells responding to a stimulus, regardless of how intense the individual response of each cell is). So, an analogue response is like a continuous scale, but a digital response is binary—either the cells pass the required threshold and respond, or they don’t (see the Jeknić paper below for a more in-depth explanation of this concept).

The problem is that regardless of whether nociception is analogue or digital, the biology will look the same on a Western blot or other similar protein or cytokine quantification techniques. Consequently, we are unable to delineate between the two states and miss large amounts of key information to how these systems work. To overcome this limitation, new techniques and approaches are required to determine whether nociception is analogue or digital.

Unfortunately, as Hutchinson went on to explain, even nociception appears to be both analogue and digital. The first study used an adapted model of neuropathic pain in rodents who were also expressing a green fluorescent protein in their microglia. This provided a window for Hutchinson and his team to look at the same cells in real time and determine what was changing proportional to the amount of pain behaviours experienced by the animal. After nerve injury, there were changes in the density, velocity, and appearance of the microglia. These changes were distributed across all cells and were proportional to pain behaviours—which suggests an analogue response.

But Hutchinson’s group also had another system running at the same time: hyperspectral imaging. This method involves shining light onto biological samples from the spinal cord and analysing the changes in colours that we observe—like pulse oximetry on a much larger scale. “This let us visualise biology in brand new colours,” Hutchinson explained excitedly. “There are no labels here, just the endogenous autofluorescence of biology shone with lots of different colours of light.” A machine learning model was applied to the autoflurorescent images to determine which pixels were changing proportional to the amount of pain expressed at the behavioural level. Overlaying these images with the biology revealed an all-or-nothing (digital) response involving glia, neurons, and the extracellular matrix.

So, based on these results, pain is both analogue and digital, and it’s not all just about the cells. This provides further evidence about the complexity of nociception and pain.

Prof Mark Hutchinson at podium, APS President, Ms Trudy Maunsell, seated

Now you’re just being ridiculous

If Hutchinson’s point about the complexity of pain wasn’t already clear enough, he used a great example from Ted Price’s group at the University of Texas at Dallas. Hutchinson explained how Price’s group focused only on receptor-ligand pairs in the dorsal root ganglion (DRG). That is, Price’s group used transcriptomic analysis to examine all the ligands released from cells in the DRG, and all the receptors present on cells. They then paired up individual ligands and receptors to determine how much potential communication was occurring just in the DRG.

Price’s group found 133 signalling pairs where neurons tell glia what to do and 199 signalling pairs of glial ligands communicating with neurons. Taking just these known factors, we are faced with a best-case scenario of 280 combinations of molecular pairs just at the level of the DRG. Worst case, it’s 2332. To quote Hutchinson, “that’s crazy complicated… there are more pathway signalling combinations than there are stars in the universe. And that is just at the level of bidirectional neuronal-glial communication at the level of the DRG at one timepoint.” However, Hutchinson isn’t put off by this complexity. Rather, he uses it as evidence for why we must do better at translating research to improve the lives of patients.

Prof Mark Hutchinson at podium, APS President, Ms Trudy Maunsell, seated

How do we get better at translating our work?

Hutchinson highlighted a fantastic resource from the American Association for the Advancement of Science called Convergence, the result of reviewing other communities and learning about how they tackled this challenge. This work has identified the need to create communities of practice with a translation-focused culture, as well as the development of both education and people skills for individuals within these communities. The former focuses on intellectual intelligence while the latter focuses on emotional intelligence. However, a crucial part of success in these communities was collaboration and targeted funding.

Hutchinson spoke about his own experiences of applying the Convergence principles within the Centre for Nanoscale BioPhotonics (CNBP), likening his time there to a real-life version of The Big Bang Theory. Many successes of the CNBP could be put down to experiential collaborations—bringing people together in communities for more than just collaboration in a laboratory. Those familiar with the show will know several academic innovations were inspired by conversations around a dinner table.

Bringing people together in a collaborative environment is not the only necessary step in improving translation, Hutchinson noted. A key element within these large collaborative communities is trust, something missing in many areas of the Australian research sector. Another element is changing how we train the next generation of researchers. There is a need to move away from the traditional model where students are trained in one thing and one thing only: individuals need to be skilled in a multitude of domains that allow for greater impact.

But perhaps the biggest challenge in improving how we translate our work is ensuring the work has real-world impact on the life of consumers, as an idea is worth nothing until it has an impact. Hutchinson acknowledged this may be challenging for academic scientists but encouraged them to return to a key principle of consumer engagement: “nothing about us without us.” In recent years patient and consumer involvement in research has improved significantly on an international scale; it is now Australia’s turn to make consumers a central figure in all research we undertake—from electrophysiology through to clinical trial design.

Pain Solutions Alliance: A new hope

Hutchinson dedicated the final section of his lecture to a potential solution for creating a collaborative, translation-focused community. This solution leverages off a vision described within the National Strategic Action Plan for Pain Management of a new institute for pain research. According to Hutchinson, such a vision is a perfect opportunity to begin working collaboratively across institutions and borders to achieve meaningful impacts.

Together with what he described as a “coalition of the willing”, Hutchinson introduced the audience to the Pain Solutions Alliance, a group driven by the vision that all Australians shall live unburdened by pain. The Alliance will place an emphasis on connecting science discoveries to deliverable impacts by drawing existing research hubs, pain centres, and communities of practice and applying the Convergence principles. For the vision to succeed, it will require consumers, researchers, health professionals, industry, and government to unite and propel the discovery and delivery of effective pain solutions. Importantly, these solutions can’t focus solely on new drugs or medical technology—they need to go all the way through to social prescriptions.

Hutchinson concluded the lecture by challenging the audience to think about the future, noting the world will not stop because we have not solved the pain problem. He posed the question of what we will still be trying to fix in 2032, and whether we can use the next decade to come together and deliver on the promises we have made—and continue to make—to consumers.

Lincoln Tracy is a postdoctoral research fellow in the School of Public Health and Preventive Medicine at Monash University and freelance writer from Melbourne, Australia. He is a member of the Australian Pain Society and enthusiastic conference attendee. You can follow him on Twitter (@lincolntracy) or check out some of his other writing on his website.

Related reading

Gosnell ME, Staikopoulos V, Anwer AG, et al. Autofluorescent imprint of chronic constriction nerve injury identified by deep learning. Neurobiol Dis. 2021;160:105528. doi: 10.1016/j.nbd.2021.105528

Jeknić S, Kudo T, Covert MW. Techniques for Studying Decoding of Single Cell Dynamics. Front Immunol. 2019;10:755. doi: 10.3389/fimmu.2019.00755

Staikopoulos V, Qiao S, Liu J, et al. Graded peripheral nerve injury creates mechanical allodynia proportional to the progression and severity of microglial activity within the spinal cord of male mice. Brain Behav Immun. 2021;91:568-577. doi: 10.1016/j.bbi.2020.11.018

Wangzhou A, Paige C, Neerukonda SV, et al. A ligand-receptor interactome platform for discovery of pain mechanisms and therapeutic targets. Sci Signal. 2021;14(674):eabe1648. doi: 10.1126/scisignal.abe1648.