Not everyone gets addicted: The science of vulnerability

Why do some people develop an addiction while others don't? In this episode, Jared Bagley, Assistant Professor of Pharmaceutical Sciences at Binghamton University,  talks through his work in addiction neurogenetics — what we currently know, what remains poorly understood, and why he thinks the overlap between neuroscience and genomics is where the field needs to go. 

Transcript

JARED: Two people try cocaine. One uses it occasionally with little consequence but the other uses frequently with huge consequences but can’t stop. The key question is why are some people at risk and some aren’t?

DAVID: What do you mean?

JARED: What puts you at risk? Is it your environment? Is it your genetics? We now  it is both. My role is to better understand the genetics.

DAVID: I'm David Hermanovitch and this is The Aha! Moment presented by Binghamton University. Thank you for joining us today as we discuss a topic that impacts millions of families each and every year, but sometimes the discussions kind of carry a mystery along with it. And that topic is addiction. When we tend to talk about addiction in terms of one's environment, their choices, their access to potentially harmful substances — and those things absolutely matter when discussing this — but today we're speaking with someone who studies how our DNA may play a role in determining how liable we are to addictive substances and behaviors. Jared Bagley is an assistant professor at the Binghamton University School of Pharmacy and Pharmaceutical Sciences, and this is what he studies. So Jared, thank you for coming on and sharing your insight.

JARED: Yeah, it's great to be here. Thanks for having me.

DAVID: So I'll start us off really quick just to drive home just how prevalent this issue is. And I'm sure those who are listening, they may already have some ideas in mind, or those who, unfortunately, have had to deal with this. But this is according to the American Addiction Centers — 48.4 million people in America ages 12 or older have had a substance abuse disorder in the year before this data was collected. And these are the 2024 numbers. And to put that in perspective, that's about one in every six people. And of that 48.4 million, about half and half — alcohol and drugs. So, obviously, to drive it home even more, just how prevalent this issue is, how important your work is, and how your work can help bring a little more clarity to addiction. So, first of all, just broadly, in your words, what is it that you study in regards to figuring out the role that genetics play in addiction for individuals?

JARED: Yeah. So we've known for quite a long time that genetics explain a lot of the risk for a substance use disorder. So if you're asking the question, why might one person be at more risk than the other? Certainly, as you mentioned, environmental things come into play. Access to drugs, of course. But we know genetics play a major role as well. And on top of that, we really want to understand the biology of addiction because we really need to figure out better ways of treating it. Those statistics you talked about are just the tip of the iceberg about how bad it looks when you think about the impact of addiction both on the person suffering and on society as a whole. And so going from the idea that, well, genetics explains a lot of the risk, to actually understanding specifically, well, what genes in the genome are explaining this risk. How do they impact the brain when you have the wrong version of that? Not the wrong version, but the version that might put you at more risk for an addiction. And so going off this idea that genetics play a substantial role, we want to get to that next step — naming the specific genes, understanding their function and role in the brain, particularly. And to do that I use research animals, specifically mice, and mice have a few key advantages. One, when you're talking about genetic studies, they're great — what we call a platform for genetic research. And two, they will perform a lot of behaviors that look similar to behaviors people engage in both when they're taking drugs recreationally, and also individuals that take drugs and qualify for a substance use disorder. We can kind of model that behavior in mice. And we know when they do these behaviors, the brain functions that are driving the behavior are quite similar to humans. So this is considered a great model for the neuroscience of addiction too, but we can also study these behaviors across a population of genetically variable mice. And so one of the key behaviors that I do in my lab is called self-administration of drugs. And so we can put the mouse into a test box, present them with levers, and the mice will press the levers out of genuine curiosity or accidentally, and they'll get an infusion of drugs when they do so. And they will often rapidly learn to press that lever specifically to get infusions of drugs. But when we do this type of test over a genetically variable population of mice, we see that some mice take a ton, take a lot, some take almost nothing or nothing at all, and kind of everything in between. What that tells us is that the genetics, the genetic diversity of these mice, is driving differences in their drug intake. And so this looks like a great way to start to identify specific genes that are causing this difference. And so the data I get out of these types of studies, in combination with some advanced analytical techniques, allows me to start identifying specific genes on the mouse genome that look to be causing these differences in drug taking. Now, this is relevant to humans potentially because many of the mouse genes that we can look at have a very similar function in the human version.

DAVID: That's very interesting. And as we talk about how some mice responded — you know, they needed more and more, and some had no real desire at all — just put that in more human terms for me. And the way my brain goes to is, you know, my grandpa — he was a smoker, and he lived with us for many years, many, many years. And he was a smoker for decades. He never quit, never took any breaks. He was a smoker for decades. Compare that to, I had a coworker at a former job of mine where he truly was someone who, if he wanted to have a cigarette, he would have a cigarette, and then he would put it away and he wouldn't touch it for however long he wanted, until he was like, "I want another cigarette." He had a lot more control over nicotine and, you know, in taking nicotine and smoking cigarettes. So that's sort of where my brain goes. So it's very interesting. Are there any broad takeaways? I know this is probably a very ongoing study and ongoing research, but are there any broad takeaways thus far in terms of potential for some answers, or at least potential for even further research?

JARED: Yeah. And I should say, I started this work as a postdoc, actually, here at Binghamton, in the psychology department. So this was work done under the professor David Yentsch, and I'm kind of continuing similar lines of research in my professorship. But what we initiated — this big study across all these genetically variable mice, allowing them to self-administer drugs — has directly led to the nomination of genes that, as a scientist, I'm going to hedge a little bit, but look to have the potential to be causing these behavioral differences. So we came across a gene via this analysis called "Neuron Navigator One," and there's not a lot known about that gene, but as the name suggests, it's helping neurons navigate through development and find the right way to set up networks and things in the brain. And when you nominate a gene like that through the data that we had, you're at a decent level of confidence, but as a scientist, you want much more. So then what we did is we went in and we manipulated that specific gene in what's called a knockout model, meaning we deleted that gene in mice. And then we can test those mice that lacked that gene versus mice that have it. And when we did that, we found that not having Neuron Navigator One caused much greater drug taking at that point. At that point my confidence is super high in that gene. And what we can do after that is think about ways to follow up. So when we're talking about this — back to your question about, well, what is this leading to, what insights is this leading to? It's the idea that we can find these genes, get some level of high confidence that they're doing what we think they're doing, and then explore their function in the brain. And that's really the frontier. I think one of the frontiers of addiction genetics is not just naming the genes and the genetic variants that drive differences in the gene functions, but also isn't the key question: what's going on in the brain because of these genes? And that's one of my biggest curiosities. So I'm really a mix of a neuroscientist and a geneticist. I'm pretty much a 50/50 mix. And so what I'm doing now is thinking about, well, how might these genetic elements — like genes and other genetic ways of thinking about the genome — how does that impact key brain physiology as well?

DAVID: Has there been any like challenges — in your reasoning, challenges or things that surprised you where you maybe got a result that kind of took you a little bit by surprise, or something that you had to overcome?

JARED: When we say we allowed the mice to take drugs, that's actually intravenous drugs. This requires the implantation of an I.V. catheter. So this is a very technically challenging form of research. And I think we still have the world record for number of mice included in a drug self-administration study intravenously. We were the first to even — or among a few groups to think of a study of a large scale that is required for this kind of genetic stuff — to think it was even possible. So getting past that hurdle was both, in some sense surprising and a great relief, because you never want to be limited technically as a scientist. It's very frustrating, right? You have a great question, but you just can't pull it off. So that was one. The other thing — it didn't come as a surprise, but when you actually see data plotted out after a big study and it's right there in front of your face, and you can visualize the differences across mice, that was awesome. And because it showed us that this was a good approach, and it was just startling. It was startling to see that genetics could cause some mice to take literally nothing, and some mice to take quite a lot of drugs over these sessions. And like I said, everything in between. So back to your point about knowing people that can take a cigarette here and there, or some that seem to not be able to moderate their use as well — a lot of that is likely explained by their genetics. And you can probably find a person that kind of fits every category in between of use levels, ability maybe to stop when things are getting consequential for them. And so this is really what we call a continuous trait. And we know that genetics cause it to be continuous. And so at some point you get to a level of use and a level of an inability to stop when the consequences get big, that now a doctor will call you a person with substance use disorder. So there's some kind of threshold on this continuous distribution of drug taking and inability to stop when things get bad, that now you're in a territory that's really bad, where you're going to experience really bad outcomes. And to see this kind of continuous distribution represented across this genetically diverse mouse population — which is really fascinating to look at — one of my favorite graphs ever produced, nerdy as that sounds, I rank my graphs. And it's just awesome to see that we have this excellent genetic model to go off of.

DAVID: The Jared Bagley graph tier list will be forthcoming from The Aha! Moment. So just looking forward — because, you know, like I mentioned and as you alluded to, there are millions upon millions of people in America that struggle with this. And you alluded to how it may possibly guide future treatments and prevention. And that would be amazing. But just a little bit more about that — what would I guess, putting yourself in the shoes of someone who, I don't know, a policymaker or something like that — what do you see as the benefit, or how can this information be used to both help treat people who currently are already dealing with a substance use disorder, and/or prevent people from falling into that in the first place? I have a feeling this would potentially have more to apply to prevention, more so than treatment. But how do you view the future for both of those?

JARED: I agree that this could be used as a prevention mechanism potentially. And the way you would do that is once you understand enough about the genetics and people — and hopefully my mouse work will inform us of this — you can actually genotype people, maybe before they've even tried an addictive substance, and say your genetics tell us that you're at a high genetic risk for substance use disorders. And maybe through some combination of just telling them that, maybe some kind of preemptive, maybe therapeutic approach — this is not really my field of expertise — but you could imagine that could be quite a powerful thing to say to someone that could potentially prevent some people from going on and exploring drugs in a way that leads ultimately to a substance use disorder. So that's kind of one element of the preventative hopes we have for this type of information. But to your other point of, can it be used to treat people that have already developed a substance use disorder? That's my greatest hope. If you think about, well, how do we develop new medications to treat substance use disorders — we really don't have a lot of medications. And if you talk about any disease physiologically, you know, I consider this is a specific thing going on in the brain that's not quite right, and it's leading to these really bad outcomes. So this is a disease process physiologically. But if you don't really have a great understanding of all the little mechanisms going on — like the nerdy stuff — scientists want to talk about, like, oh, this gene does this to this neuron. And look what happens — once you get a really comprehensive physiological understanding of something like that, you can rationally design drugs. You can go, okay, this gene makes this protein that does this. What if we design a drug to block that protein? So the more you understand about what we call the pathophysiology — what's going wrong physically in the brain — the better chance you have of developing new pharmaceutical agents that could potentially help people. And I would add on to that — there's a therapeutic approach. I think people are probably aware that, you know, people might go to a therapist, they might go to a drug rehab, or they might be in peer groups like 12-step meetings. And I think even understanding the biology and the genetics at a higher level could definitely help us, help inform us about how to maybe better develop therapeutic approaches. So it's not necessarily just some pharmaceutical hope — it's a comprehensive hope that any avenue of treatment that might be effective can be informed, and we really have a good physiological understanding of the problem.

DAVID: So for me, if there's one thing that I take away from this research, it's that understanding the genetics can really help stop a problem before it starts, but also definitely has really good potential application for those who currently struggle with a substance use disorder. You know, Jared, what do you want people to take away from this research?

JARED: Well, one thing people might think about is, should you stigmatize someone with a substance use disorder? As we've seen society stigmatize people suffering from this in the past — and currently, I would say. And what I really want people to understand is that addiction is a state. It's not who you are. And so do not look at someone with a substance use disorder and think they're hopeless, or they're generally weak, or this is a moral failing, or they really don't want to quit. That's another big one. Many people really, really, really want to quit. They really don't even like doing the drugs — like even at a basic pleasure level, they kind of lost all that over these years, but yet they can't, right? There's something very odd going on — I don't want to say odd — but there's certainly something going on in the brain in people suffering from this that is causing a kind of a major malfunction around their ability to decide what to do, right? And their brain always wants to decide to do drugs, basically, for the most part, much more so than they should. But you can get them out of this, right? And we want to figure out how to do that better.

DAVID: Thank you. That was Jared Bagley, assistant professor at the Binghamton University School of Pharmacy and Pharmaceutical Sciences. I'm David Hermanovitch, and this has been The Aha! Moment podcast presented by Binghamton University. Thank you for listening. We'll be back next month. The Aha! Moment is a Binghamton University podcast. Subscribe to us on Apple Podcasts, Spotify, YouTube, or wherever you listen.