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, , 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 – the man on fire syndrome – and extrapolated to broader populations such as small fiber , 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 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. It actually is fun to disseminate what we do – at least fun in my eyes – to the larger public. And I think it’s part of our job since we not only are investigators generating new knowledge, but I hope that scientists in the trenches view themselves as advocates of science and of pain research.

In terms of how one does it, the way I do it is to try and explain as I would to an aunt or uncle or cousin who is a history teacher or who works selling insurance what we’re doing and why it’s important and why it’s exciting. And the sense of excitement is important because that resonates.

What I try and do in a discussion of that sort is to use terms that nonscientists can understand. A nonscientist may never has heard of a or BDNF, but they do understand if you tell them that a sodium channel can be thought of as a tiny molecular battery that enables nerve cells to generate impulses. And you can use examples. So when I talk to a general audience, I will explain that Nav1.7 sets the gain on DRG neurons, but what that means is, in a sense, it is the volume knob like the volume knob on a radio, but in this case, the volume knob on pain signaling nerve cells. So those are a few things.

I also think it’s important to be clear, especially when dealing with people interested in a disease or a disease process to connote the sense of excitement that we all have and connote a sense of hope but not to overpromise. We don’t want to generate unrealistic expectations.

And so, I will use wording like, “I know you would like a new treatment now, and I can’t promise that. It will not happen this month or next month, and it probably will not happen next year. Maybe not even for the year after. And I can’t give a schedule, but what I can tell you is that there’s a small army of talented, energetic investigators working on this. They’re all aiming in the same direction, and there’s progress being made month by month.”

I’ve found that that will deliver a sense of hope and generate real interest without overpromising. So those are a couple of the things I do when talking to a general audience.

DP: So I guess that would lead me into my next question. We can both agree on the fact that disseminating this knowledge is so important. But how important do you think it is for the general public to know more than just the clinical applications of our research?

SW: Well, I personally think it’s very important. My own view is that people – at least some people, many people – are inherently curious. Certainly, young boys and young girls are inherently curious, and I think most of us who do research would agree that there’s an element of fun in science.

DP: Absolutely.

SW: So, it’s very important to not only communicate the clinical applications but the fact that we are studying the most complex computer in the universe – the human nervous system – and it’s a wonderful challenge. So I think it’s very important to communicate the science too, and there’s an operational objective here, which is we need a new generation of scientists. We need curious, bright, young women and men. They’re out there. We need them, and we need to share our excitement about science. It’s a wonderful career.

DP: Obviously, you gave some nice advice to junior researches. So we’re told to buckle up our seats. Can you tell us a bit about what obstacles you’ve endured throughout your career in the field of pain research that are maybe unique to the field of pain?

SW: Well, there obviously are generic issues in any sort of medical research. I think it’s fair to say that pain research has some of its own unique challenges. One is almost a societal issue, that if you tell people you are doing research on multiple sclerosis or spinal cord injury, that conjures up a picture of somebody in a wheelchair. You can see the disease, and people you’re talking to can empathize with it. And they get it that it’s a disease with a very firm cellular and molecular basis. That’s not always understood in terms of pain.

So, as a community, I think we’ve had a challenge getting pain recognized as a disease target that is high priority and needs attention. If one is interested in developing new pain medications, here we have a disorder or a set of syndromes in which we often rate pain intensity with an NRS, 0 to 10, with all the noise and jitter involved in that sort of rating scale. As of today, there is no yet generally accepted biomarker. The animal models are not strongly predictive of human therapeutic response, and the placebo response is substantial. So those are very real challenges, and they’re part of the landscape, but the important lesson is they don’t mean that pain is an insolvable puzzle. I truly believe we can unravel the mechanisms and that we can understand pain both at higher cerebral levels and sub-cerebral levels, peripheral levels, and that we will develop new and more effective non-addictive therapies.

DP: So you’ve covered the obstacles that you’ve endured that are specific to the pain field, but could you tell us a bit more about obstacles that you’ve endured throughout your career that aren’t necessarily specific to one unique field?

SW: Sure. Science is challenging. It’s competitive. It’s demanding. And so, how does one build a career? One thing that seems trivial and that one will hear again and again, but I think it’s very important, is to follow your passion.

Scientific research, as I said, is very demanding. I was chairman of at for 24 years, and as a predictor of success of young individuals, clearly skill and intelligence are needed, but in addition, when I thought about what is it that enhances the likelihood of success, one is passion and focus.

Another issue is time management. I think it’s fair to say that for every scientist, there are more experiments to be done than any of us can ever do. And so we need to be very strategic scientifically, but we also need to think about time management because for a scientist – certainly for a clinical scientist but also for a scientist in the lab – time is a very important commodity. In a sense, it’s coinage – you can’t spend the same hour twice.

Another thing that I think is important is to recognize – especially when you’re young in your career – that we all have options, and we need to think very strategically. By that, what I mean is, we don’t have to say yes to every opportunity. We should say yes to the opportunities that fit with our ultimate goal.

And an example is, years ago, when I was a new assistant professor, I had a colleague. He was at another very, very distinguished university. We were both new assistant professors. I was at Harvard/MIT. He was at another great institution. We both were MD/PhDs, and we periodically would talk on the phone. And this individual would say, “Steve, what are you doing to position yourself to become dean?” And I would say, “well, nothing, I’m doing my experiments.” I said, “what are you doing to position yourself to become dean?” And without any hint of humor, he listed all the committees he was on, both national committees and local committees. And I said to him, “well, why do you want to become dean?” And he said, “Steve, because that’s how you become university president.”

Now, that individual now is the president of a major university. And I periodically talk with him on the phone, and I say, “boy, I envy you. You get to build 10-story research buildings,” and he says, “Steve, I get to envy you. You get to do experiments and be with graduate students.”

And the reason I tell that story to my trainees is, his decision was right for him, and my decision was right for me. And everybody has decisions to make. And I think one needs to keep that in mind. You don’t have to take the path of least resistance. You need to think, what do I want out of my career, and how do I get there.

DP: Amazing. I think that’s great advice. And being in the first year of my DPhil, I’ve already noticed that. There are so many amazing opportunities here, and so, obviously, if I did every single one, I wouldn’t be able to sleep.

Waxman: So my question is, what are you doing to position yourself to become dean?

[Laughter]

DP: Well, if dean was the endpoint.

SW: I’m joking.

DP: But I think you bring up such a good point because I think there are so many things that I, myself, find very interesting, and I would love to do if I had the time. But thinking more long-term, I think one of the biggest things in the first 6 or 7 months of my program has been trying to figure out, what is my long-term goal. And that’s been a struggle in and of itself, but I think as opportunities arise, trying to think of whether or not it’s truly something that aligns with my passion; that’s something that definitely distinguishes an opportunity that I would be interested in pursuing versus one that is maybe interesting but not necessarily one that would help me long-term as well.

SW: And Danielle, as you and other investigators who are growing their careers move along, you’ll meet lots of different role models who’ve structured their careers in different ways. And it’s important to spend time with them, grab that cup of coffee with them, and decide which path is the best one for you.

DP: Exactly. And I think even when you have the understanding of what your end goal is there are so many different ways to get there. And so I think knowing that it’s not this rigid path that you have to follow. You don’t have to do X, Y, Z in that order necessarily to get what you want to get. But I think you’re right having those important conversations with people who have been through that before is something that is so important.

Well, thank you so much for taking the time today to talk to me about your experiences studying pain, studying rare diseases. And I think as a trainee, and especially someone who is so early on in my research career, I have benefitted immensely hearing about the toolkit that I can use to figure out the path that is best for me and how I can seek the right opportunities.

I think one thing that really stuck to me was hearing about this translation of our research to the general public and maybe those who are affected by the disease and how excitement is something that is so important because I know that if someone talks to me about anything and they’re excited about it, it almost makes me excited about it, and I go home and sort of look it up on my own. And I think that’s a great thing to remember not only as a young researcher but someone who’s quite senior in their career is to maybe never lose that excitement because that’s what keeps yourself but others interested in the work as well.

SW: Yeah, you know, I’m sitting here in my office in New Haven, and on my wall is a picture of two children. They have inherited erythromelalgia. They both carry the L858F mutation of Nav1.7, and these children cannot survive in a room at 68 degrees Fahrenheit because that triggers excruciating pain. They’re homeschooled. They can’t go to a public school or the playground or the mall. And their picture is on my wall because that adds for me, and the people who work with me, a human aspect of the disease or even a human aspect of understanding, in general, pain signaling, electrogenesis in DRG neurons and how pain is produced in a mechanistic sense.

But it’s also useful because none of us has a record in which every experiment works. All of us have days when things don’t go right, and particularly for the young people in my lab, on those days when things don’t go right, it’s useful for them to see that picture on the wall knowing that it’s okay. We’re going to go back. We’re going to try again. Because our work matters.

And to all the senior people but also the young people in the pain research community, I just emphasize your work matters.

DP: Well, I think that’s such a positive note to end on. So thank you again so much for taking the time to interview with me today. I had a great time and I am so excited for everyone to hear this podcast as well.

SW: Good speaking with you, Danielle.