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Transcript of PRF Podcast with Stephen Waxman Transcript of Podcast with Stephen Waxman Danielle Perro (DP): Hi, everyone, my name is Danielle Perro, and I was chosen as one of the PRF correspondents for this year’s NeuPSIG program. As a part of this program, I have the great pleasure of introducing leaders and interviewing leaders in the field of pain research. Now, I know that NeuPSIG has ended, but today I have the great pleasure of interviewing Dr. Stephen Waxman from the Yale School of Medicine. His research focuses on the application of molecular techniques to study neurological diseases, especially spinal cord injury, multiple sclerosis, and neuropathic pain. Thank you, Stephen, so much for being a part of this interview today. So my first question for Stephen here is, could you tell us a bit about the work that you’re doing and what principles from the work that you do can be generalized to other pain conditions and how we study them? Stephen Waxman (SW): Well, I am interested in pain in a reductionist sense. I would like to understand the molecules involved in generation of pain, particularly chronic pain, and so, my laboratory largely focuses on sodium channels. And some years ago, having done more on sodium channels and pain in in vitro models and animal models, cells in a dish, having done more on those topics than any sane person would want to hear about, we launched a worldwide search for families with inherited neuropathic pain. As neurologists, we see neuropathic pain all the time, but we never see families; they’re incredibly rare. We knew they’d be very rare if they existed. But we looked for them with the following rationale: If you think about the history of modern medicine, rare genetic diseases can teach us very important lessons that are applicable to the broader population, and a good example is the discovery of the statin drugs, which manage blood lipids, and have been a major advance in public health. The development of the statins was propelled by the discovery and study of incredibly rare families with inherited hyper- cholesterolemia – families where everybody was having heart attacks in their twenties. These rare families pointed the way to the culprit genes, to the culprit molecular pathways, and that was an important step forward. And so, we, years ago, began a worldwide search for families with inherited neuropathic pain. We have found them. We surveil a population of close to 3 billion, and from that, there are just a few dozen families that, in a sense, represent the experiments of nature that we can cull out from this large population. But they’ve taught us an immense amount, and they’ve validated the role of three sodium channels – Nav1.7, Nav1.8, and Nav1.9 – in human pain as major players. So that’s been one major theme. And then we’ve moved from rare genetic diseases such as inherited erythromelalgia – the man on fire syndrome – and extrapolated to broader populations such as small fiber peripheral neuropathy, which is seen all the time in broader populations. And again, these channels play an important role. So that’s been a major theme. Building around that or beyond that, I’m interested in pharmacogenomics – how can we predict in a precision medicine, genomically-guided way, which medication will work best in any given patient? And we’ve become interested in the issue of pain resilience, and from some of our families who’ve inherited neuropathic pain, we’re now studying intra-family, intra-individual differences in the pain experience. And we’re beginning to pinpoint pain resilience genes. We have a lot more work to do, but that’s been a really interesting and productive approach. You mentioned the question of principles derived from our work. I think there’s an overriding principle about how one studies human subjects. There’s no question that big data, big cohorts, large clinical trials, can teach us a lot, but when I was training, one of my mentors, Norman Geschwind, reminded me that there’s a counterpoint. And that point is that carefully studied single patients or carefully studied small families can teach us a lot. And in fact, I subtitled my talk at the NeuPSIG meeting “Big Lessons From Small Families.” And I’ve just written a commentary in which I’ve talked about the fact that small families can act as pointer-kindreds that teach us important lessons. DP: So looking forward to the future then, do you think that this genomically- guided medicine is the way that we will be better understanding complex diseases? SW: I don’t know that I would say it’s the way. It certainly is a way. And I’m persuaded that it is not unrealistic to aim for a precision medicine, genomically-guided approach to pain management in the future. We’ve got an immense amount of work to do, but we’ve begun to at least identify a small number of gene variants that confer strong responsiveness to existing pain medications or insensitivity to them. So we have a lot more work to do, but we’ve taken the first steps. DP: Absolutely, and it sounds like a very exciting field of research. And looking forward, I think, it will be interesting to see in what way it interacts with our current practice of medicine. SW: Yeah, in our case, it involves human genetics; then atomic level molecular modeling of ion channels, drug targets and their gene variants; then modeling in disease-in-a-dish models, both DRG neurons in a dish and iPSC-derived sensory neurons. And using all of these things in the aggregate to predict drug responsiveness. So, it’s challenging science, but it’s been productive in our hands. DP: Well, that’s very exciting to hear. So just to flip the coin here, we’re talking about some obviously very positive things that have come from your research, but studying rare diseases, have you experienced many frustrations with this process? SW: I’m smiling because “frustrations” is an understatement. There are frustrations in any type of research. If you’re studying a rare disease, there are some unique frustrations. One is finding appropriate individuals, finding families. We surveil, as I said, an overall population of close to 3 billion to cull out a small number of families that are likely to teach us important lessons. And not only do you have to identify the families, but these are human beings. They’re not laboratory rats, and they carry with them the complexities of human beings. They get sick or family members get sick or they have other inter- current issues, and so, it’s just a built-in set of challenges. I think it’s also fair to say that in the United States, in the UK, and in much of Europe, we live in highly regulated societies. There are lots of regulations and rules, and we have to and do follow the rules. We work closely with ethics committees, human investigations committees. It takes time, but it’s important to do things right. It can be done. Another frustration is when you’re studying a rare disease, there’s not a lot known when you begin. And so, you in a sense have to create your own knowledge base. In some cases, even rudimentary aspects of the clinical phenotype are not well understood. And so, we’ve learned that we have to pay an immense amount of attention to phenotyping and even what I call deep phenotyping. So those are frustrations. And putting them all together, what it means is that translation, doing human research can take a long time. I advise young scientists to buckle up their seatbelt for a long ride. Sometimes, a bumpy ride. But I also emphasize that if you’re strategic and persistent, you can make the translational leap. DP: Do you think that collaboration plays a role in the success of your studies with rare diseases given the fact that you had mentioned that at the base level there are sometimes that we just don’t know a lot of the basics about the disease phenotype? And so, have you found that collaborative efforts have aided in that? SW: I’m smiling here because MIT Press just published a book in which I tell the story behind the science in terms of identifying pain genes. It’s called “Chasing Men on Fire.” But one of the chapters in that book is called “Crossing Borders” and it explains to nonscientists why we’ve had to establish collaborations that are international. Why, if I’m based in New Haven, am I collaborating with investigators in Beijing and in Maastricht? After all, there are good people in the building next door. And what I explain is that collaborations involve strategic planning. Sometimes the other group has resources or access to patient cohorts or something that we don’t have and vice versa. And so one builds collaborations on the basis of strategic planning. But one also builds collaborations on the basis of shared interests, shared passions and a lot of trust. When you build a collaboration, you’re sharing data, you’re sharing patients, you’re sharing techniques, and we’ve thought a lot about how to do that so that everybody comes away a winner. So you need to just find the right chemistry, and along the way you make friends. DP: How do you make such complex topics easily digestible by the general public? SW: That’s a great question, Danielle.
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