Pushkin.

Pain is terrible, obviously, it's kind of the classic terrible thing, and having medicine to treat pain is great.

But the strongest drugs we have for pain, opioids, are infamously addictive, deadly.

Even more than ten thousand people die every year in the US from prescription opioid overdoses.

Opioids are addictive because they act on the brain to blunt our sensation of pain.

But pain doesn't start in the brain.

It starts in the nerves in other parts of the body, and then it gets relayed to the brain.

So for decades scientists thought it would be amazing if we could find a molecule that was really good at blocking pain in the nerves before it gets sent to the brain.

That way, we could make a pain drug that is as strong as opioids but is not addictive.

And earlier this year, for the very first time, the FDA approved exactly that kind of drug.

I'm Jacob Goldstein and this is What's Your Problem, the show where I talk to people who are trying to make technological progress.

My guest today is Stephen Waxman.

He's a professor of neurology, neuroscience, and pharmacology at Yale.

Stephen's research helped to pave the way for that newly approved pain drug.

It's a drug called suzettrogene, and in particular, Stephen has spent decades studying ion channels.

Ion channels are these little gaps in nerve cells that let charged particles ions in and out of the cell.

Suzettrogene works by blocking one particular ion channel.

As you'll hear later in the show, Stephen thinks suzetrogene is a promising start, but he also thinks there's still a lot of work left to do to develop better pain drugs, and the story of how we got to cizetrogene reveals a lot about how science works, and how drug development works, and ultimately about how the body works.

Well, how did you get into pain?

You know?

When I was an mdphd student, I had the privilege of doing a four month stint at University College London with Patrick Wall.

Wall was the father of modern pain research, and so I spent four or five months with him.

So I got to work at his side, and I realized that pain is not only a very important challenge, but also a puzzle box that presents intellectual challenges, but that could be solved.

Huh.

Tell me a little more about what you experienced in those four months, Like, was there a particular moment or some particular problem that was intriguing to you.

Well, what became clear to me is that pain is a hierarchical experience.

You may experience it peripherally through your peripheral nerves, but that the pain messages are then processed and modulated in the spinal cord, relate upwards to the lower brain than to the cortex, and so it's an experience that is processed at many levels, and at each level if you take a reductionist approach, it seemed to me that you can take it apart and understand it.

Huh.

So you start thinking of pain as this sort of hierarchical phenomenon, and is there a particular level of the stack that you decide to focus on.

That's a great question, you know, Jacob.

When I was a young new scientist, an mdphd student resident then a new assistant professor at MIT and Harvard, I wanted to study grand philosophical problems at the mind interface.

What is consciousness?

That sort of thing.

Yeah, and I published some papers in the cybernetics literature and got awards for them.

But I came to the conclusion that while that was a very important challenge, that it was those issues were not going to be resolved during my professional lifetime, and so I retreated from grand philosophical questions to much more soluble, concrete questions that could be solved during my professional lifetime.

So that's what I did.

When I talked to students trainees, I relay this story to them because they have a choice.

Do they want to attack large, philosophically grand questions or work at a more fundamental, reductionist level.

There's no right answer.

This was right for me, and they have the opportunity to make your own choice.

So you go from big consciousness ultimately to very small right like ion channels, which about as small as you can get in medicine, right, and ion channels obviously mostly what we're going to talk about here, right, a tremendous amount of your work.

So that's correct.

How did you get into ion channels?

Well, I got into ion channels because of my interest in axons nerve fibers.

While I was an undergraduate, I spent nine months at University College working with a man named Jays zed Young.

He discovered the giant axon in the squid, and so I became interested in how axons work.

And the axon is part of the nerve cell.

The axon is the long nerve fiber that extends from the nerve cell.

Our nervous system consists of one hundred billion nerve cells in every one of us.

It's the world's most complex computer.

And each of the nerve cells has an axon that connects it to other nerve cells.

So I was interested in axons, and it rapidly became clear to me that I had to understand how axons work and the driver of activity in axons nerve impulses bup, bup, up, up up up up is ion channels, sodium channels that act as molecular batteries, potassium channels that act as molecular breaks.

Huh.

So these are basically channels in the membrane of the cell through which ions charge particles move, causing the nerve cell to fire or not fire more or.

Less, that's right.

And when they fire, a nerve cell produces what's called an action potential or a nerve impulse, and it's the pattern of firing of nerve cells that they use to communicate with each other.

So you're doing work on ion channels as a way to understand the behavior of nerve cells.

You're also doing work on pain, right, And there has been, by the time you get into the field a history of work on the relationship between ion channels and pain.

Right, So when you get into the field, what do we know?

What does humanity know already about that relationship?

Actually, when I got into the relationship between ion channels and pain, not much at all was known.

I mean, we had lytocane and novacane, right.

So lytacane and novacane are sodium channel blockers.

We all know that when they're injected locally, no pain.

That's what you get when you get a cavity filed.

Right, that's correct.

But if you put those drugs in the form of a pill and administer them systemically, they would affect sodium channels in the brain.

So there is double vision, impaired balance, sleepiness, and confusion.

And so that doesn't work.

And so this is a really interesting arc of science.

Sodium channels were discovered by Hodgkin and Huxley.

They did the work right after World War two and published it in nineteen fifty two, and their studies were in the giant axon of the squid.

And then fast forward to our lab in around nineteen eighty five, we were able to record similarly from axons from rats and then humans.

They're one fiftieth the size of the squid giant axon, and we were able to see that not only were sodium channels there, but that the abnormal firing of peripheral nerve that underlies pain was caused by a particular type of sodium channel.

So at some point, as I understand it, you get a call about a neighborhood in Alabama where a lot of people have an unusual experience of pain.

Is that true?

Did somebody call you on the phone?

Is that how that starts?

That's correct.

We were taking two approaches.

One was a mechanistic approach from ground up, looking at pain signaling neurons that we could study in a dish and dissecting them channel by channel, asking what did the various channels do to cause abnormal firing and pain.

You can think of a neuron a symphony of multiple ion channels working in a highly orchestrated way, and so at that point, we had identified three sodium channels as potential very very important participants in pain signaling NAV one point seven, NAV one point eight, and NAV one point nine.

So these are just the names of different ion channels that behave differently under different circumstances that we have in our nerve cells.

That's exactly right.

Yeah, So that's the sort of ground up mechanistic work that we were doing.

But there's another top down approach beginning with whole human beings and trying to see using genetics as there are there particular genes, particular proteins related to a disease, in this case, the disorder of pain.

And let me back up a bit.

If you think about the history of modern drug development, why look around the world for families with rare inherited diseases.

The answer is that rare diseases, inherited diseases often teach us important lessons about more common disorders.

And a good example is the statin drugs.

The statin drugs which have revolutionized cardiovascular medicals.

I'm a fan, I take one every day.

Many of us do, and they were developed on the basis of the discovery and then study of incredibly rare families where everybody who was having heart attacks in their twenties.

Huh, those families had inherited hypercholesterolemia.

Their genes pointed the way at the relevant molecules and informed of drug development.

So it's basically like, if there's some family of people that has a strange version of a common malady, let's look at their genes and maybe that'll point to a way to treat that malady in people without the mutation.

That's the basic hypothesis.

That's exactly right.

You just did it.

Yeah, so you want that, but for ion channels, that's what you're looking for as you're doing your lab work.

You want this sort of genetic mutation that might show a clinical application.

That's correct.

So we launched a worldwide search for families with inherited neuropathic pain pain due to inappropriate firing of peripheral nerves.

Neurologists see patients with neuropathic pain all the time, our clinics are filled, but we never see families.

So it's typically not a genetic problem.

Right, It's like you have diabetes or something.

It's not you inherited it from your mother.

That's correct.

So we launched this search and what happened was interesting.

In the beginning of two thousand and three, February or March, a colleague member of my team brought me the latest issue of the Journal of Human Genetics.

There was an article out of Beijing, China on two families with men on fire syndrome inherited from lalgia, each with a mutation of navy one point seven.

The man on fire syndrome inherited erythrommelalgia is a really interesting disease.

Most physicians have never seen a case, never will, but if you see it, you remember it because it's so striking.

These people feel that they're on fire.

They describe searing, scalding, burning pain that's triggered by mild warmth, putting on shoes, wearing a sweater, going outside when it's seventy two degrees fahrenheit.

The pain is so bad some patients ask for limbs to be surgically amputated, which does not help.

But it's excruciating pain.

So here was an article out of Beijing by a very good group of academic dermatologists and geneticists saying, we have two families with the man on fire syndrome, each with a mutation of Navy one point seven.

And my initial response to my colleagues my research team was to say, think, gee, we've been scooped.

This is not a good day.

And I said to my colleagues, stay away from me.

It's a good day for humanity, but not a good day for your lab because somebody beats you.

Yeah, exactly.

And my initial response was stay away from me.

I'm going to be pretty grumbly.

And just as a reminder any of you one point seven, that's the that's the ion channel that you had identified as associated with pain in the lab.

And here's a kind of clinical validation of that, but coming not from you but from some other scientists.

Yeah, from Beijing, China.

But when I closed the door and read the paper over a cup of coffee, I realized they had not told the full story.

They had told just the first chapter.

And the reason is this.

When you when a neuroscientist finds a or an ion channel, biologist finds a mutation of an ion channel, that's just the beginning of the story.

Because the presence of the mutation doesn't necessarily establish that the mutation is causing disease.

What you need to do and what's industry standard is you make the mutant channel, you put it in cells, and you find out does the mutation cause a change in activity of the mutant channel, and then hopefully you can then take the mutant channel, put it in cells where it normally is expressed, and ask does it change their behavior.

They hadn't done any of this stuff.

So essentially they had identified a correlation, but they had not demonstrated that causation.

Right, yeah, and they hadn't done it.

These were very, very fine academic dermatologists.

We've subsequently become friends.

One of them spent the sabbatical in my lab.

But so what needed to be done was what I just said, to make the channel and study its physiology.

And we had the channel in our freezer because we had done all the work on the normal channel.

So what would have taken anyone else a year took us a few months.

We made the mutant channel, we found that in the mutation causes the channel to be overactive, and at that point we published it and shortly thereafter got a call or an email from the Erythrum Lalgia Association.

This is a small group of patients with erythrumlalgia.

Which is man on fire syndrome.

Yeah, and the large family is in Alabama, Okay, and I sent the team down to Alabamas.

We spent a week examining these patients, getting detailed histories, and most importantly, getting blood for DNA analysis.

The Erhythmologia Association gave us a gift to support our research, but much more important than the funding gift, the monetary gift was the gift of DNA and these precious histories for correlation with it.

And it's been a very, very a warm relationship.

It's taught me a lot about how patients really are, are more than patients their partners in our research.

What did you learn from those patients in Alabama that you didn't know already?

What we learned was now we had a pedigree of around sixty individuals in five generations.

Half of them had the mutation.

That's what you expect for a mutation of this sort.

Every patient you had the mutation had the man on fire syndrome.

None of the patients without the mutation had it.

And now putting it together, this was rock solid.

This is as good as it gets in terms of genetic validations.

So this mutation that all of these people have effects the sodium channel in AV one point seven, right, one of the ones you had identified, and is it right that that inspires you or other researchers to think reasonably, Okay, let's try and make a drug that blocks that channel and see if it will treat pain or Jacob.

This is really interesting and it speaks to sort of the sociology of science and the way science moves forward given the fact that it's very expensive.

So we had mechanistic validation from studies in a dish for a strong strong role of both NAV one point seven and NAV one point eight in pain, and we argued that both were good targets.

In some ways NAV one point eight could have been regarded as a stronger target, but what we had for NAV one point seven was this very very remarkable picture of genetic validation.

And in addition to our patients with men on fire syndrome, there were other families found a few years later with loss of function of NAV one point seven.

These families don't make NAV one point seven, and those people don't feel any pain, painless childbirth, painless tooth extractions, painless bone fractures.

We basically, if you have two much action in NAV one point seven, you have a lot of pain, and if you have no action there, you have no pain.

That's correct, very compelling set of evidence.

It is compelling, and most of the biopharma industry followed that evidence and studied one point seven or tried to develop drugs that block NAV one point seven.

It was harder to convince biopharma to study NAV one point eight.

The physiological evidence was there, but the genetic validation wasn't.

We'll be back in just a minute.

Back in the aughts, Pfizer and other pharmaceutical companies started trying to develop drugs to treat pain by blocking NAV one point seven, that key channel that Stephen and other researchers had identified both in the lab and in pall with man on fire syndrome.

The preliminary results were promising, but kind of shockingly, in larger trials, the drugs targeting NAV one point seven did not seem to be effective in treating pain.

It's not entirely clear why the drugs didn't work, but this kind of thing in fact happens all the time.

Drugs that seem perfectly designed just don't end up panning out in the real world.

But remember NAV one point seven wasn't the only key channel involved in pain.

There's also NAV one point eight, and one drug company decided to bet on one point eight.

The company that's taken this across the goal line as a company called Vertex.

I'm now advising them.

They looked at one seven, and they looked at one eight.

They had a number of failures, and they kept going.

They invested an immense amount of money when we worked with Pfizer.

My estimate is that they invested well over two hundred and fifty million dollars in their one seven blocker before abandoning it.

Vertex has studied many compounds, they have very gifted scientists, and they made the decision to stay with it.

They invested much more than that, and they stayed with it over over twenty plus years.

So I don't know who the decision makers were, but they made the right decision.

So they decided to work on compounds that blocked this channel one point eight, another one that you had identified.

I know you weren't involved in all of it, but more or less, what is the story of developing that drug.

So what this company did and others did is they had their target molecule.

The question is can you identify a molecule potential drug that blocks it, and you can put those molecules into a cell.

There are robots that will look as you screen hundreds of thousands of compounds, asking is there something that silences that molecular battery one seven or one.

Eight and you wanted to silence that and nothing else, right, that's correct part of that and not have some weirdo side effect that's gonna make people sick.

That's absolutely crucial.

But with using these robotic technologies, it's possible to find one or two that work.

And then you say to your chemists, Okay, this is our lead compound, make it better, make it orally available, give it the right absorption and excretion compounds properties, et cetera, et cetera.

And so that's how it goes.

And then you still have a lot of work because you need to demonstrate in a dish that the compound silence is the activity of pain signaling neurons.

Then usually go to rodent models, sometimes non human primates, and then the human trials.

It's a long, long process and they.

Managed to get through this process, right.

So there is this drug suzetragene.

Yeah, it got FDA approval for at least some indications this year, correct.

Yeah, I think there were a couple of milestones.

Yeah.

One was the demonstration even prior to FDA approval that it produced a statistically significant reduction in pain in humans.

So let's talk about that moment.

So, you know, it's this incredible long road and they have to find the compound in testing animals, and they do phase one and face two, and then finally there's the giant phase three trial.

Right, so you're a phase three trial with hundreds of patients and then the results come out, Like when did you learn the results of this pivotal trial.

I learned of the results of this pivotal trial when a medical journal, the New England Journal of Medicine, said, Steve, there's been this pivotal trial.

You've done all the work on one eight identifying it as a target, and when we published the results of the trial, will you write an accompanying article.

We have a series of articles on the science behind the clinical trial and they asked me to do that.

You really didn't know until the New England Journal asked you to write an editorial.

I didn't And what did you think when you saw the results?

I thought, my.

God, we're getting there.

We're not there, but we're getting there.

If this can be repeated, it's a very important step forward.

Tell me about both pieces of that.

That's like two things, like, we're getting there is something, but we're not there is also something, So what is the we're getting there piece?

We're getting there was why I regard their study as a milestone.

It was proof of concept that by targeting a peripheral sodium channel, which is a step toward non addictive, non opiate pain therapy, one can reduce pain in humans.

That in itself is a real milestone.

And just to be clear, what was the finding specifically of this trial, what was the outcome?

These were two groups of patients with abdominoplasty that's tummy tuck surgery and bunyan ectomy, and the reduction in pain was statistically significant, about as large as was seen with opiates.

It was vicd in right, it was some fairly standard h yep.

So it's like this basically is like for these patients, this is about as good as vicotin, which is actually great because as we know, opioids are addictive and it's a huge problem.

And so if you can reduce pain in a non addictive way, that seems like quite a happy finding.

So that is a happy finding.

It's a contribution to clinical medicine.

But for me, as a researcher, it's also, as I said, proof of concept, and it raises the question, Okay, we have proof of concept.

Now we build on it and build even better drugs.

And that gets to the issue of that you asked, why still more work to do?

And the point is that the drug was as good as vicodin.

It reduced pain by two points on the ten point scale, but it did not totally abolish pain, and so why did it not work better?

So we're working and I'm assuming that within the biopharma industry there is great effort to We're working on the question of can you do better?

And if so, how would you do it?

So the first question is when you see less than full pain relief, is it because the drug to in this particular drug is less than optimally designed in terms of its pharmacokinetics, pharmacodynamics, distribution through the body.

And if so, then it should be possible to build a better drug, or is there a biological ceiling.

This is the best you can do by targeting that particular molecule at a one point eight.

So we're looking at that right now in the lab.

Right now, is there a notion that there are other channels that might be complementary.

If you target more than one channel at once, you might get improved outcomes.

So anybody trying one point seven and one point eight, that's an obvious question, would you like a job?

So we're going through the exercise of doing that in a dish in a very quantitative way.

Let's block one point eight plus one point seven.

We could do it with one point nine.

There's a channel of interest.

It's a break on the firing of these sales called kV seven.

These are very, very challenging experiments, but we're doing it very systematically, and so in a year I hope we have an answer for that.

My prediction is number one, there will be next generation drugs that are more effective.

But my caveat to it is they may involve a combinatorial approach, blocking several channels or modulating several channels, and we have a lot of work to do to get there.

If you think about that future, whenever it is five years from now, ten years from now, twenty years from now, like, what's that world look like?

What's that world look like?

You know?

Weekly daily, I receive letters more frequently emails from patients, or more frequently from their loved ones, particularly parents, concerned doctors.

I have a patient with whatever, and their pain is untreatable.

There's just nothing for them.

And I envisioned a world where we can treat these people.

It's an important goal.

It's hard to quantitate it.

I certainly can't put a timescale on it, but there's an immense need and I'm encouraged.

I tend to use my words very conservatively and cautiously.

And there's one particular teenager whose father periodically emails me, is there anything for my daughter?

I used to tell him that I hoped we would have a non addictive treatment for chronic pain for people like his daughter.

I now can write back confidently and say I can't say how long it's going to take, but there will be.

And so that's the way I look at things.

And we've come a long way.

We'll be back in a minute with the lightning round.

Okay, now we're going to finish with the lightning ground it's going to be a little bit more random, but still more or less on point.

Is it possible to learn to be more resilient to pain?

Oh?

Absolutely, Look we send marines to Tampa June to toughen them up, and they learn to be resilient to pain.

There are various types of monks who manage their pain beautifully.

Cognitive and behavioral therapy work.

So there's no question that there are psychological aspects to pain, and that provides an important lever on pain.

Having said that, here we are in the year twenty twenty five.

Those techniques have been refined again and again, and we still have just a highway of patients who have unrelieved pain, and so we need pharmacological approaches.

Is there something I can do to be less angry when I bang my head or stub my toe.

It's remarkable.

I'm not generally an angry person, but I get so angry for a moment when that happens.

You know.

I follow a family with a man on fire syndrome, and there are two children who have severe pain.

They've had a hard time dealing with it.

But their mother wrote to me some months ago and she said, one of the children is having a very hard time because he fights the pain, and her other child, through therapy, has learned to quote, go with it, and there's a lesson there go with it.

When I'm taking away from that is go with it.

Well, that's the word the mother used.

What is something about pain that is currently poorly understood or entirely mysterious that you wish were better understood.

Well, one major problem is how pain becomes chronic.

So if you stub your toe or burn your finger, there is hyperactivity of those sensory neurons that is appropriate and protective.

You withdraw your your finger.

That's good pain, that's the pain we need.

That's good pain.

But if you have diabetic neuropathy and develop a painful neuropathy or chemotherapy and doce neuropathy, or if you have a nerve injury, those same nerve cells generate barrages of impulses in the absence of a painful stimulus, and the details of what drives cells to become chronically hyperactive are still unknown, So that's something we need to understand.

We need to understand when that happens.

Are their changes also in the spinal cord, lower brain, and higher brain.

All these things are understudy, but they are important mysteries and they will be solved.

Stephen Waxman is a professor of neurology, neuroscience, and pharmacology at Yale.

Please email us at problem at pushkin dot fm.

We are always looking for new guests for the show.

Today's show was produced by Trinamnino and Gabriel Hunter Chang.

It was edited by Alexander Garriton and engineered by Sarah Bruger.

I'm Jacob Goldstein and we'll be back next week with another episode of What's Your prob