Editor’s note: The second North American Pain School (NAPS) took place June 25-29, 2017, in Montebello, Quebec, Canada. An educational initiative of the International Association for the Study of Pain (IASP) and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), and presented by the Quebec Pain Research Network (QPRN), NAPS brings together leading experts in pain research and management to provide 30 trainees with scientific education, professional development, and networking experiences. This year’s theme was “Where Does It Hurt and Why: Peripheral and Central Contributions to Pain Throughout the Body.” Six of the trainees were also selected to serve as PRF-NAPS Correspondents, who provided firsthand reporting from the event, including interviews with NAPS’ six visiting faculty members and summaries of scientific sessions, along with coverage on social media. This is the fourth installment of interviews from the Correspondents, whose work is featured on PRF and RELIEF, PRF’s sister site for the general public. See the first, second, and third, and fifth installments of NAPS interviews.
Anne-Marie Malfait, MD, PhD, is a professor in the Department of Medicine (Rheumatology), and director of the Laboratory for Translational Research in Osteoarthritis, at Rush University Medical Center, Chicago, US. Malfait studies the mechanisms of osteoarthritis pain using animal models. She sat down with PRF-NAPS Correspondent Jessica Ross, who recently completed her PhD at the University of Cincinnati, US, to discuss her career path from academia to industry and back, as well as some of the latest thinking about osteoarthritis pain. Below is an edited transcript of their conversation.
Before coming to Rush University Medical Center to study osteoarthritis pain, you worked in industry. How did you enter that setting, and what was your experience like?
I was briefly a clinician, after which I did a PhD in biochemistry and then a postdoc. I also did some immunology work at the Kennedy Institute in London. I was then recruited by the pharmaceutical industry in 2001 because I was working on a hot target called aggrecanase, an enzyme with a key role in the degradation of cartilage.
I was in industry for seven years—and I loved it! There were many reasons why, but mainly because in industry you work in teams with fantastic researchers. Very good scientists are hidden in industry; we don't know them because they don't publish much, but they're experts in what they do. The research at companies is multidisciplinary so you work with chemists, crystallographers, and drug developers, all highly specialized people who are extremely good at their work.
When I came in, I was relatively young, and all of a sudden I was a group leader with men who were twice my age and who had expertise in topics that I had never even heard of. But everybody had the same goal of making the project succeed, so we all worked together, and I really liked that. I learned so much, and it was some of the most interesting work I've ever done. Learning all these new things was like being at a university all over again.
But it becomes hard after a while because there is less freedom. Your team may have to stop working because the company decides to prioritize other teams in order to meet goals and milestones. People are frequently shifted to another team or are laid off. If anything, working in industry made me more pragmatic—I'm always making sure that my work is translatable.
How did you transition from industry to Rush University Medical Center?
I wanted to study osteoarthritis in a chronic model, which I didn’t have the opportunity to do working in industry, so I left, which was hard. I looked everywhere for university positions, but everybody turned me down—they said I needed funding. But I couldn't get funding because you can't apply for funding while you're still working at a company, so it was impossible.
But Rush has a very long tradition in osteoarthritis, and Dr. Joel Block, the head of the rheumatology department, which is a clinical department, gave me the opportunity to join his division, grant funding or no grant funding.
Was that a person you knew?
No. I knew of him, but someone else I knew brought me in contact with him. He is a clinical researcher in osteoarthritis and is still my boss. It's great because he always says to me now—it's only eight years ago since I came to Rush—that it would be very hard for him in the current environment to take someone on without funding.
Is the moral of the story that networking is important?
It's very important. For two years I did nothing but go to every meeting—I even paid my own way to a few of them—and I would just go talk to people. I had a lot of help from many people. For example, some of them reviewed my first R01 grant proposal and funded it at some point. I'm very grateful for that; you really need that type of support and to spend your time building relationships.
I love the path my career took, but it was not obvious. Working in the pharmaceutical industry is potentially a good fit for many people. If you're going to be a principal investigator in an academic setting, in the end it's more work—at companies you do have the weekends off. True, you might be laid off when you return on Monday, but you don't have the endless deadlines and pressures you face in an academic setting; people don't realize that sometimes. So you do have to love it; otherwise you'll be miserable.
Let’s shift gears now to talk about some of the science. How did you get going on your work with the destabilization of the medial meniscus (DMM) model, a surgical model of painful knee osteoarthritis (OA), to learn more about this disease?
While I was working in the pharmaceutical industry, where I started studying pain using the DMM model, I began working with Jeffrey Mogil as our outside consultant. He suggested that we test mechanical allodynia, and he did the very first experiments in this area. Industry was wary of this model, because of the time it takes to develop OA.
At this time, our studies were only performed up to eight weeks following injury, because to do this work out to 16 weeks took far too long for a company, where the preference is for faster models like intra-articular injection of complete Freund’s adjuvant (CFA) or more drastic surgical models. When we said we didn’t think those paradigms appropriately modeled OA, we were asked whether we really needed to capture OA. That was always a really big question, and it still is—does it matter whether you use a disease-specific model or not? I'm starting to think that it really does matter.
How do you determine the relevance of an animal model?
For OA, the elements that we really need to capture to make the models translationally relevant are chronicity, along with cartilage breakdown, subchondral bone sclerosis, joint space narrowing, and osteophyte formation, which happen in many people and probably earlier than we think. People are starting to make a distinction between pathology of the joint in OA and the illness of OA, which comes with pain. It would be incredibly important to model that.
Regarding the distinction between OA joint pathology and OA pain, there are people who have severe joint pathology on their x-rays but don’t feel much pain. What is your thinking about this issue?
It's very important to keep in mind that x-rays don’t mean much in that regard because they really just image bone and not soft tissue.
There's increasing awareness that OA is probably heterogeneous. For instance, there is obesity-related OA, different types of injury-related OA, and what people call “garden variety” OA—OA that happens with age.
The microenvironment—what is happening in the joint—is probably very important to determine what will happen with pain. That's why it's essential to study the relationship between the joint and the nerves; the type of stimulus that reaches the nerve will depend on whatever environment in the joint is triggering the whole process. And the microenvironment is different depending on, for instance, whether there is a really big injury versus repeated small injuries. For example, people who use drills all the time get OA, but that’s a whole different joint milieu than in somebody who, say, jumps off stairs, like a lot of young people do, and tear their anterior cruciate ligament (ACL). So the nervous system must process what’s happening in the joint slightly differently. I would like to study this by using different animal models to see if the signals coming from the joint in these various injuries are, in fact, different.
You mentioned in your NAPS talk that anti-nerve growth factor (anti-NGF), which had safety issues in clinical trials of OA pain, was tested in animal models of pain but not in animal models of OA. What is your perspective on this?
It's probably very important to test drugs in disease-specific models. The NGF trials were abruptly stopped because a small number of people developed a rapidly progressive osteoarthritis. It turns out that only occurred at the highest doses and in patients also taking non-steroidal anti-inflammatory drugs (NSAIDs). We still don’t understand the mechanism behind it. Some people say it's because the pain is gone, and so people walk too much and put too much weight on a compromised joint. This may be the case, but it’s just a hypothesis.
There haven't been any mechanistic analyses, but a recent study in an OA model found that a specific anti-NGF antibody, tanezumab, clearly accelerated joint damage. The anti-NGF approach is very exciting, and if we can find the mechanism and get around the safety issue, these could be excellent drugs. Lowering the doses of the drugs and no longer combining them with NSAIDs will be important, as will implementing some risk mitigation strategies, for example, by excluding patients who may be at risk for accelerated OA.
What do you think of the debate at NAPS over peripheral versus central maintenance of pain?
It's an artificial dichotomy. What I haven't seen discussed is that many of the central changes are reversible, so it would make a lot of sense to study why these changes don't reverse in some people. In OA, there's evidence that when you do a total joint replacement, previous changes in the brain seen with imaging are reversed. These are small studies, but they are fascinating. So isn't that an argument that a peripheral drive keeps the pain going? Yes, there are exceptions, and one can study those exceptions. But if chronic pain is being maintained in the periphery, we could probably target that more safely and easily than the central nervous system.
Additional Reading:
Chemogenetic inhibition of pain neurons in a mouse model of osteoarthritis.
Miller RE, Ishihara S, Bhattacharyya B, Delaney A, Menichella DM, Miller RJ, Malfait AM
Arthritis Rheumatol. 2017 Jul; 69(7):1429-39.
Spinal microglial activation in a murine surgical model of knee osteoarthritis.
Tran PB, Miller RE, Ishihara S, Miller RJ, Malfait AM
Osteoarthritis Cartilage. 2017 May; 25(5):718-26.
LaBranche TP, Bendele AM, Omura BC, Gropp KE, Hurst SI, Bagi CM, Cummings TR, Grantham LE 2nd, Shelton DL, Zorbas MA.
Ann Rheum Dis.2017 Jan; 76(1):295-302.
Miller RE, Block JA, Malfait AM
Curr Opin Rheumatol. 2017 Jan; 29(1):110-18.
Emerging targets for the management of osteoarthritis pain.
Malfait AM, Miller RJ
Curr Osteoporos Rep. 2016 Dec; 14(6):260-8.
On the predictive utility of animal models of osteoarthritis.
Malfait AM, CB Little.
Arthritis Res Ther. 2015 Sep 14; 17:225.
Malfait AM, Ritchie J, Gil AS, Austin JS, Hartke J, Qin W, Tortorella MD, Mogil JS
Osteoarthritis Cartilage. 2010 Apr; 18(4):572-80.
Tortorella MD, Malfait AM, Deccico C, Arner E
Osteoarthritis Cartilage. 2001 Aug; 9(6):539-52.
