Ellen Goldbaum: Arin Bhattacharjee didn't grow up with dreams of becoming a scientist.

Arin Bhattacharjee: I was a kid who liked sports. I really wanted to be a soccer player when I grew up.

Ellen Goldbaum: But he was smart and curious, and he had a knack for science. An undergraduate degree in biology led to a PhD in pharmacology, and today, as a neurobiologist at the University at Buffalo, he's developing a novel approach to pain relief that could have a massive impact on millions of lives.

Welcome to Driven to Discover, a University at Buffalo podcast that explores what inspires today's innovators. My name is Ellen Goldbaum, and I will be your host for Season 2, Episode 1: Opioid-Free Pain Relief.

So, Dr. Bhattacharjee, you wanted to play soccer as a kid. Now you're a neuroscientist. Can you tell us how you got from there to here?

Arin Bhattacharjee: Yeah, so I grew up in Western Canada. I was someone who just loved to just play sports, play games. I wanted to be a soccer player when I grew up. And when reality set in that I'm not going to be a soccer player, my mom said, "Look, what are you going to do with your life?"

I had done an undergraduate degree in biology up at the University of Alberta. I then actually spent another year and a half doing a pharmacology certificate. And then I worked at the university bookstore selling computers.

And again, mom was pushing me, she was like, "Look, are you sure you just want to sell computers?" So, I liked biology and I decided to pursue a PhD degree, and I was fortunate enough to get an opportunity down at the University of South Alabama.

When you start graduate studies, you actually get to rotate in different labs to see, you know, where is your fit. The second rotation was a rotation working on something called ion channels. These are little, sort of, protein holes in the membranes of cells that let ions flow through, like potassium and sodium. I was studying ion channels in pancreatic beta cells, which are the cells that release insulin. So my research was about diabetes, and this is stuff that I thought was really, really, really fascinating.

But when you go do a postdoc, you have to expand your horizons, you have to learn new techniques. And so it was a neuroscience lab at Yale University. So I did my postdoc there. And so that path for me, going from somewhere where I really wanted to be a soccer player, I really wanted to do that. As a kid, I was a dreamer and I liked to dream. I imagined scoring the winning goal in a World Cup game. I imagined stuff. And it turns out that science was really a great path for me to use that strength.

Ellen Goldbaum: Very interesting. So for people who don't know, maybe you can give us a simple definition of ion channels.

Arin Bhattacharjee: Okay. So if you remember from high school biology, you have a cell, and a cell is enveloped by a membrane. That membrane doesn't allow things to come in. But if you put these little proteins, or these little sort of cylindrical types of holes, they will allow a specific ion to come in. Sodium channels are channels that allow sodium in. Potassium channels are what allow potassium to flow out, actually.

Ion channels are found in electrical cells. Neurons are electrical cells. The heart is an electrical cell. Your muscle’s an electrical cell. So why do you not put your finger in the electrical socket? Because the current from the electricity is going to go through your neurons, it's going to allow all these ions to flow, and you're going to get electrocuted. Right? So ion channels are super important for how neurons talk to each other.

Ellen Goldbaum: What is it about ion channels that led you to study pain?

Arin Bhattacharjee: Pain was a real interesting way to study these channels, because other sensory systems, as you’re looking at me or you're listening to me, it's always on. All of those senses are always on. But pain can't be on all the time, and we don't want it to be on all the time. It's only in these certain moments where you have injury, that's when pain has to manifest. And these ion channels that I was studying became really, really important for looking at that.

Ellen Goldbaum: So now you've made this incredible discovery with one of your students, I believe. Tell us in lay terms what this discovery about pain was and how you and your student got there.

Arin Bhattacharjee: Okay. So it's actually quite a few students over a period of 12 years since I've been here at UB. The one thing we noticed when we were looking at pain-sensing neurons is that when you have a pain stimulation, when there's some injury, the ion channels that I was studying, they start to move. They were actually becoming internalized from the membrane. And so once they become internalized, these neurons are now starting to go berserk, if you will.

So one of the things that we thought we wanted to try to do is, could we prevent these channels from moving? And so there's a tool that we created in the lab, and these are called lipidated peptides. So peptides are small protein fragments. They're built together with amino acids. And then what we do is, we put a little fat group on that peptide. And once that peptide, if you add it to the nerve endings, they actually start to get into the membrane of the neurons, and they stay there.

And what we're able to do is block the interactions of these ion channels with the proteins that bring them inside. And so the student, his name is now Dr. Rasheen Powell, he's a postdoc at Harvard. When he was a graduate student in my lab, he did these key experiments to show that these peptides could actually block pain.

And there's a lot of things that actually block pain. So, for example, if you've gone to the dentist, they may locally apply an anesthetic, novocaine. Novocaine works great when the dentist is doing the procedure, but when that novocaine wears off, that's when you say, "Listen, can you give me something else?" Our molecules actually can last a long time.

The other thing with novocaine is that you can't feel anything. You're totally numbed. But what our molecules do, because we're really looking only at pain-sensing neurons, is we're able to prevent pain transmission, whereas other transmission, like touch, all of that is fine.

Ellen Goldbaum: When you say that it could stop pain for a long time, what do you mean?

Arin Bhattacharjee: Yeah, so this is actually a really, really great question. Novocaine lasts about 30 minutes. Okay? The longest-lasting local anesthetic is about six hours. Our peptides actually work for three weeks.

Ellen Goldbaum: Wow.

Arin Bhattacharjee: And so we think, really great for these acute pains, but now we can think about chronic pain as well.

Ellen Goldbaum: Yeah. Talk a little bit more about a specific, like, what do you think is one of the best cases to talk about pain that could be solved for that long?

Arin Bhattacharjee: I mentioned to you about dental applications, but there's a lot of people who get surgeries. For example, bunion surgery.

Ellen Goldbaum: Yeah, I recently had that, by the way.

Arin Bhattacharjee: So how did you manage your pain relief?

Ellen Goldbaum: It was awful. They gave me hydrocodone. I took it once and I got sick and never took it again.

Arin Bhattacharjee: Yeah, so, during the surgery, did they put you under anesthesia?

Ellen Goldbaum: Yes.

Arin Bhattacharjee: Okay. So under the anesthesia, you don't feel anything. You're in la-la land. When you wake up, that seven to 12 hours is called the breakthrough pain. And they'll say to you, "I have an opioid. That's what I can give you, and here's a prescription." Okay?

Under anesthesia, what we would imagine our molecules doing, if they were approved at the time, is that we would just apply it to the area that you had your bunion surgery, and it would take you for three weeks. With no pain for three weeks.

Here's the problem with opioids beyond addiction. They cause you completely to be dissociated. You have breathing issues. They can cause severe constipation. So when you have surgeries, you want to start the rehab process as soon as possible.

But if you're sedated, you can't.

If we're able to block just the pain-sensing neurons, just the pain-sensing neurons, then we can start to imagine, if you've had knee replacement surgery or hip replacement surgery, if you've had some kind of surgery where you can now start your rehab over those three weeks. And you're not feeling pain.

Ellen Goldbaum: Okay. We chatted earlier and you were talking about your mom's experience with painkillers.

Arin Bhattacharjee: Yeah. So my mother, like many women, suffers from osteoarthritis. The medication that she was being prescribed is called a nonsteroidal anti-inflammatory drug, or NSAIDs. We all know what NSAIDs are. If you've ever taken ibuprofen, that's an NSAID. The thing about taking an NSAID daily for pain is, the way NSAIDs work is they prevent the synthesis of a molecule that causes pain, but that molecule is super important for protecting your stomach.

And so my mother was suffering from a bleeding ulcer, and she actually had to go into the emergency. She actually could have bled to death because of the bleeding ulcer. So she's off of that NSAID. What does she do for arthritis? What many seniors across this country and across the world do is they get injections of what are called steroids into the joints. And so our molecules can be used, if they're in that three-week to maybe even four-week window, we can actually be an additive or a replacement to those steroids.

Ellen Goldbaum: Okay, talk about the benefits of what you're developing from an addiction standpoint.

Arin Bhattacharjee: So our drug does not affect your brain. Our drugs affect the site of the injury, where the neuron endings are, and those are called the peripheral nervous system. Our drugs will never get into the brain. They'll only stay at the nerve endings. And actually that makes them very safe. There's a saying, you know, about 90 to 95% of all drugs fail clinical trials because they cause a lot of side effects. So if you take a pill, it's getting into your body, it could affect your liver, it could affect your kidneys, it could affect your brain. What we're doing is we are providing local, long-lasting pain relief, and there would never be an addiction potential.

They say the opioid epidemic started from the surgical theater. There are 80 million surgeries every year performed in this country. Eighty million surgeries means that there's going to be a lot of need for pain relief. And you have at the moment two types of drugs: these NSAIDs that can put a hole in your stomach, or these opioids. And so what we think we can do is provide you pain relief in a totally different way.

Ellen Goldbaum: That's amazing. But one thing I don't understand is actually how do you take this drug?

Arin Bhattacharjee: Okay. So it depends on the actual pain condition. So if you have osteoarthritis in your joints, they'll literally take a needle and inject the steroid into the joint. But for bunion surgery, we could imagine that this would be applied like a gel over the wound before you suture up. If it was burn patients, that could be a cream. And so it really will depend on the actual pain condition and then the formulation then will be adjusted accordingly.

Ellen Goldbaum: So another fascinating part of your research is what you discovered about gender differences with pain. What have you found about that and how does that impact your research?

Arin Bhattacharjee: The NIH mandated that experiments that are being done include both sexes. So for years, decades, basic researchers would use males, because they didn't want to deal with the cycle, because that would confound their data. And that was just really, I think, a terrible idea. So the NIH mandated that, so we were doing our experiments and we noted that, in our research, that males and females, the way they responded to our medication, depending on when it was given, was different.

So if we preemptively gave our peptides to females, the pain actually was better treated versus males. After injury, giving our medication, or giving any medication, females have a tougher time to respond. And so there has been many drugs that have failed the clinics for pain relief, but if the preclinical trials were using males as their model only, you can imagine that can be an issue.

And so, I've been asked, well, what if your drug only works for one sex versus the other? Well, that's 50% of the population, so that's still pretty good! Right? But we need to appreciate that pain is different in males and females, and that will help us for drug development.

Ellen Goldbaum: Okay, so before I let you go, I understand that, as exciting as the pain relief work is, your focus on ion channels is also leading you down some other exciting paths?

Arin Bhattacharjee: The drugs that we have developed to date are targeting two different ion channels that are found in the peripheral nervous system. So we're now looking at channels that are in the brain. And the ion channels that we're looking at are very, very important for cognition, Alzheimer's disease, epilepsy. And really, I'm very excited by this work. We are still thinking about pain, but because we're looking at these channels within the central nervous system, we can start to imagine. And that's been the theme.

Ellen Goldbaum: Well, thank you so much for talking to us today. This was really fascinating.

Arin Bhattacharjee: Well, thank you so much for giving me the opportunity to talk about my research, talk about myself. And just, to anyone, you know, neuroscience is really cool.