Transcription of Dr. Elissa Chesler and Dr. Vivek Kumar for the show Investigating Addiction & Preventing Polio #285

Dr. Lisa Belisle: Today it is my great pleasure to have with me Dr. Elissa Chesler who is an associate professor at the Jackson Laboratory in Bar Harbor and director of the lab’s Center for Systems Neurogenetics of Addiction. She studies disease complexity and behavioral science with an emphasis on the genetic and genomic analysis of alcohol and substance use disorders. Also I have with me Dr. Vivek Kumar who is an assistant professor at the Jackson Laboratory and who studies the genetics of addiction. Thanks so much for coming in today.
Vivek Kumar: You’re welcome.
Elissa Chesler: Thank you.
Dr. Lisa Belisle: I know it was kind of a long travel down here from the Jackson Lab to Portland, so it’s a big deal that we have you here, and not only for that reason but also because the NIH gave you a large grant back in the summer, $11.7 million, I believe?
Elissa Chesler: Yeah, that was our Center for Systems Neurogenetics of Addiction. That gives us a lot of opportunity to bring investigators in to use new research resources and tools and approaches at the Jackson Lab to study addiction-related behaviors across lots of different areas of addiction.
Dr. Lisa Belisle: For you it’s also been important to have conversations out in the general public about addiction. I know Dr. Kumar that you actually gave a Ted Talk on the subject.
Vivek Kumar: Yeah, I did.
Dr. Lisa Belisle: Tell me a little bit about that and why is it important for you to be doing this with those of us in the general community?
Vivek Kumar: My advocacy started because I read an op-ed piece that was published in the Bangor Daily News about a woman named Colleen Singer. She died less than 40 miles from where I live, mainly because she didn’t get the care and the treatment that she needed. It really was a failing at a societal level, at a medical level to provide the proper treatment, I felt, and I was doing fundamental research in basic biology of addiction, but obviously there is a huge gap in terms of what we know scientifically and what is implemented at the policy level, at the state level, and at the society level.
I made it a mission to go out and talk about this disease, to fill this void, this gap. I talk about addiction as a chronic disease, addiction should be treated in a longterm basis much like diabetes, much like hypertension, and I talk about the etiology of addiction, the treatment of addiction and the changing of mindset from a moral failure to one that is more of a chronic disease that anyone could be vulnerable to and anyone could have, just like diabetes or hypertension.
Dr. Lisa Belisle: It’s my understanding that the Jackson Laboratory is really trying to do this in many areas, to cross that bridge between fundamental bench science and public health and clinical work. Is this something you’ve been interested in for a long time as well, Dr. Chesler?
Elissa Chesler: Absolutely. I think in a lot of ways as researchers we try to solve the real problems underlying the disease, the mechanisms, the discovery of new treatments, new cures, using the genome to find those treatments. At the end of the day, there’s so much more infrastructure around disease, delivering health care, and also understanding disease. For me it’s been in my education. I was originally actually an MD-PhD student. I discovered as a scientist I’d have greater impact in the lab than in the clinic. It’s always been with me that everything that I’m doing in the lab has this much broader reach to the whole world around that patient and around the society that’s involved in their condition and how it’s treated.
Vivek Kumar: I think all scientists need to get out of the lab and convey what they’re doing to the public. They get a huge amount of money from the National Institute of Health to do fundamental research, but if we don’t convey what we’re doing back to society and we don’t get involved in debates that are going on in our community, then it hurts science overall. We end up with people that don’t believe in global warming, we end up with people that doubt something that’s as fundamental as evolution, and it affects our kids, and it affects the next generation.
We’ve got to, as scientists, we’ve got to get out there, no matter what we work on, we’ve got to get out there and talk about what we’re working on and how it affects society.
Elissa Chesler: I also think in the area of addiction in particular, unlike any other disease, we tend to treat most diseases with drugs and medical interventions, but with addiction there’s a lot that comes to the individual from understanding the process of becoming addicted, for the family of understanding the experience of an addiction, and so any education that we can do about what the disease really entails might actually have an immediate therapeutic benefit. When we can understand the differences in different mice even, in terms of their tendency to ingest alcohol or self administer a drug, we’re saying that biology is playing a role in whether or not someone is likely to start using a substance, to compulsively use that substance, and have difficulty stopping using that substance.
When we can see that in mice, it helps us actually have at least for me a lot more compassion for people with the condition, a lot more understanding of this isn’t something that a person has decided, necessarily, to do. There’s some decision-making process going on, but there’s a tendency to make those decisions and a tendency for those processes to become hard-wired in certain individuals. Understanding that biology, understanding how that change takes place from experimenting with drugs to using them compulsively, I think, can help people understand when they’re starting to have trouble with that drug use and need to start thinking about or seeking help.
Dr. Lisa Belisle: When you decide to go into science it’s pretty early on that you start developing interest in a field. For each of you I’m sure there was a turning point where you decided, I think addiction is what I want to work on. Can you describe that for me?
Vivek Kumar: Yeah, absolutely. I come from the field of addiction from a very molecular area. My training was really molecular biology: my PhD was studying how genes turn on and genes turn off. When I was looking for postdoctoral fellowship, I was trying to decide what field I should go into, and then it turns out that behavior, we actually know very little about the molecular basis and the genetic basis of complex behavior. I felt it was a black box, and there’s a lot of discoveries that could be made.
I kind of picked as what are the big problems for the next 20, 30 years, and this in my opinion is one of them. Tom Insel, who used to be the head of NIMH, the National Institute of Mental Health, has this great slide where he looks at the past 50 years and mortality from different diseases. If you look at cancer mortality, it’s decreased significantly over 50 years. If you look at mortality due to mental illness such as suicide, it’s pretty much completely flat.
There is a huge amount of work that needs to be done. We need to understand the molecular, the genetic basis of these complex disorders. That’s the reason I got into the field.
Elissa Chesler: Have you ever seen a duck have a messy landing on the water with a lot of splashing and everything? I went into college, and I wasn’t sure exactly what I wanted to do. I started taking my science courses, and I took a biological psychology course, and it fundamentally changed the direction that I was pursuing. I think I wanted to do journalism actually.
Between that and this course I took in probability and statistics, I learned a lot about how we know things, how we come to know things, but also what a scientific discovery is, how we contribute to science and how the brain supports behavior, how the brain can be changed in response to experience, but also that there is this biology underlying all behavior, and that truly fascinated me. I went on to pursue an MD-PhD. I was really inspired by Oliver Sacks and reading Awakenings. I really wanted to go in the clinic and do some research and fix people.
Not necessarily fix them, but I was inspired by the cross talk between the clinic and the lab. Ultimately one thing leads to another in a career path, I think, and I just became so amazed by the tremendous opportunity to apply computation to biology and especially in the area of behavior where we have often trouble, we all know what blood pressure is. We can all measure blood pressure, but how do we measure behavior, or addiction, or depression. It’s a much more complicated problem. I was inspired by the ability to use computation to understand those things and certain new techniques in genetics that would allow us to do that in a really impressive way.
Between those two things and pursuing one opportunity after another, I really got involved in the issues around behavioral complexity. I’ve come to know a lot of people who suffer from alcoholism and addiction, and when I realized the synergies between what I can do in my lab and what’s going on in their lives, and the relationships among what we’re learning and what they’ve experienced, it’s all come together for me. I’ve just landed in this area and I’m really pleased that I am because I think it is work that has real meaning and real importance to me.
Dr. Lisa Belisle: Dr. Kumar, what are you on a day to day basis, what are you actually doing with addiction and from what I understand, mice, and that’s what Jackson Lab is known for?
Vivek Kumar: Your audience may wonder, how do you study something as complex as addiction in mice, but it turns out mice are a wonderful system to model complex diseases. Their brain structure is very similar to humans. Obviously it’s much smaller, but all the relevant regions are there, all the relevant cell types are there. Genetically we’re very similar. We share most of our genes with mice. We can have, we can put mice, and we can have very complex behavioral paradigms with mice, something that we can’t really do in humans. We can control their environment from before birth until the end of the experience.
My lab uses the classical, what’s known as forward genetic approaches. Forward genetics essentially means you take something that’s completely normal and you try and break it. We take a normal mouse, and we use mutagens to create random mutations and then we ask, what are the genes that are mutated that lead to abnormal behavior? We can use something like cocaine response, which is a locomotor, so mice run around, just like humans get hyperactive when they’re given a psychoactive drug. We use this approach.
It’s very like going back to 1950s and 60s with Seymour Benzer, which is the idea that you take something normal, you break it, and then you find what’s broken, and that gives you a clue as to how that system is actually functioning.
Dr. Lisa Belisle: I was interested when I was reading about the grant that your laboratory received, to hear that you were hoping to go beyond just treatment of addiction and really were hoping to get to a place of possibly preventing addiction. I think Dr. Chesler, maybe, they were quoting you, and you were saying that were certain traits that we look for that go along with addiction. If you can identify those traits earlier on in a person or a family, maybe something can be done before the person gets to the place where they need treatment.
Elissa Chesler: It may be possible, but we also have to keep in mind that people have understood that this is a disease that runs in families, and they’ve understood that for a long time. Most people do not need a genetic test to know, for example, that alcoholism’s been in their family for five or six generations. I think, for us, if we can understand, predict, characterize, traits like impulsivity, traits like sensation seeking, those people that really want to go out and take risks and do interesting things, those are really god qualities, but at the same time they may lead to some vulnerabilities.
The question is, does that help us when it comes time to think about prescribing drugs for pain or looking at understanding more broadly a pattern of behaviors, how we might intervene in schools or generally in development, and yet we want to be careful because these are natural traits, these are normal variation among people, and it’s only when stress, environment, drugs, and biology come together that this abnormal process starts tolling.
The question is, how do we predict it? How do we use that information without actually derailing someone’s creativity and opportunity and potential, but really to help people understand themselves better so that maybe the insight may come, oh wait, I should probably avoid this or this is getting out of hand. The earlier that happens, the more reversible the changes of addiction are.
Vivek Kumar: There are four traits that are known to be predictors in teenagers, predictors of later issues with substance use disorders. This includes anxiety, as Elissa mentioned, impulsivity, sensation seeking, and depression. If you know you have a teenager or, I have a 12 year old, with any of these issues, it would be in their interest to help them deal with something like anxiety. You help them mange their feelings, you get them proper coping skills really early on. We know that if they’re given the proper coping mechanisms early, then that leads to reductions downstream in the need to take alcohol or take illicit substances.
It’s really critical when a person starts using drugs. The brain is developing until about 25. In our society we make most alcohol, nicotine is legal at 18, alcohol is legal at 21. Marijuana will soon be legal, and these are incredibly powerful neuromodulators that are going to perturb a developing system at a really critical point. If a person starts drinking before the age of 15, their risks of alcohol abuse goes up almost four fold if they were to just start drinking past the age of 21. It’s really critical when the developing nervous system gets a drug. It’s really important to discover and keep an eye out for these predictors of later addictive behaviors and substance use disorder issues.
Dr. Lisa Belisle: Are you able to do anything with behavior modification in mice?
Elissa Chesler: That’s an interesting question. There are some studies that can be done and some that have been done to try and manipulate behavior in a manner that increases or decreases substance use. In general, especially for the kinds of techniques that we’re using, where we do larger scale genetics studies, I think, it’s an area that’s open for a lot of exploration right now. Now that we have over the past 10 years, I’d say, really made significant advances in our ability to do studies in highly complex behaviors, now is the time to ask those more complicated questions. We have the resources, and we have the computational tools to actually ask those questions well now.
Dr. Lisa Belisle: What are some of the exciting things that you’ve learned that you’ve been surprised by?
Vivek Kumar: I’m surprised every day. This is the reason I’m a scientist because I go into the lab with this idea that I could discover something new that no one else has discovered. It rarely happens, but it does happen. In one of the papers that we published as part of my post octoral work and the work that we’re continuing at the Jackson Laboratory, we looked at two inbred strains of mice. These mice were exactly identical in 1951, but sometime between 1961 and 1964, they picked up a mutation that causes a very different response to cocaine. We identified this one nucleotide out of 2.5, 2.8 billion nucleotides. That led to discovery of a gene and a pathway that people had not linked previously to addiction. It turns out that this protein and this pathway regulates structure, actually the structure of brain cells in a very critical circuit in the brain called a mesolimbic reward circuitry.
This circuitry is very critical in regulating addiction. It’s actually critical in regulation motivation. When this circuitry is perturbed, it can lead to all sorts of problems including addiction. It turns out that this gene which we cloned using cocaine response, now there’re other people who study nicotine response or study alcohol response or study food binging, have shown that this same mutation causes differences in all these different phenotypes which may seem really odd, but remember this reward circuitry is regulating a lot of different behaviors. Food reward, sex reward, these are natural rewards that this circuitry evolved to control.
It makes perfect sense that it’s not only regulating drugs of abuse, but it’s also regulating natural rewards. That was very surprising. We made a discovery with one drug, and it turns out to have phenotypes in many other domains.
Elissa Chesler: We’ve been looking at genes that play a role in multiple related behaviors. One of the things that we discovered through, we kind of sometimes think of it like dumpster diving, but we’ve taken lots of old studies in behavioral genetics and we’ve compiled the results of those studies, mostly genes that people were less interested in, and we put them in a database, and that allowed us to see where information piles up. What genes are most highly connected to different behaviors or groups of behaviors.
Doing this dumpster diving, we pulled one out that was really exciting to us. It actually is a gene that is both involved in alcohol withdrawal, but also alcohol preference. We’ve been able to show that there are genetic variants among mice that influence how this gene is expressed in response to alcohol. It actually can help us predict alcohol withdrawal, alcohol drinking. Gene regulatory mechanisms are really interesting. Although humans and mice share many, many genes in common, almost all of them, the very specific nature of that regulation differs.
Yet, we can show that this system in general is conserved from humans to mice, and that we may potentially be able to explain at least a little bit of variation in human alcohol drinking in those individuals that may experience more alcohol withdrawal. That’s something we’re looking at now. It’s always amazing to me that we have so many mechanisms of alcohol and drug response. People want to think there’s a gene for this and a gene for that. We’re really extracting millions of different mechanisms, if you will, maybe not millions, but a large number.
Different individuals are going to have different combinations of those mechanisms at play in their particular situation. We’ve got much to do to relate those to each individual and what they may need.
Dr. Lisa Belisle: Do you feel that we have become a more addicted society in general?
Elissa Chesler: Yeah. I think so. Huge predictor of addiction is stress. Alcohol drinking as well. There’s issues in the stress response. There’s also systematic issues in life stressors. When we have so many people experiencing economic distress, feeling a loss of opportunity in their lives, and a certain frustration, I think, drugs and alcohol become attractive.
Initiating is one thing. Starting to use is one thing. Having these things available, freely flowing in communities, whether it’s prescribed or street drugs, that’s just getting started. It’s what are the things that facilitate continued use. All of that is interacting with a person who may or may not be addiction prone. You can think of it as there’s a little bit of a needle there. We may be born with it set in some position, but life stress may push it closer, and drug exposure may push it closer.
Even if someone’s really not that prone to addiction, but has all the other events occur, they can too be pushed into alcohol or drug addiction.
Vivek Kumar: Addiction like any chronic disease is a result of your genetics with your environment. Our genetics are not going to change that much. That takes many generations. Our environment can change fairly rapidly. All we have to do is look at the crack epidemic or the heroin epidemic or even the opioid abuse epidemic in the state of Maine. There are correlations between economic disparity and addiction. It makes perfect sense. When people feel hopeless, they seek alternatives to ease that pain, and drugs are a very easy way to deal with that.
Dr. Lisa Belisle: Dr. Kumar, one of the things that you talked about was binge eating, which I find very interesting, because obviously as a family practice doctor, not only do I deal with addictions to nicotine, addictions to alcohol, but we now have this obesity epidemic. I’m particularly interested in why you think that we might be predisposed to this now, this particular addiction, because I think there is a huge food addiction issue.
Vivek Kumar: Comes back to the circuitry, which is this mesolimbic reward circuitry. This circuitry evolved over millions of years where…. Let me put it this way. We have an animal that lives in a nest and has to make a decision every morning, am I going to go out there and explore? The risk is I can get eaten by a predator. If I go out there, I can find a new mate, I can find a new source of food, and this balance is exploratory drive, is regulated by this mesolimbic reward circuitry, which is a survival circuitry. When we eat, we feel good. Dopamine gets released. It’s not surprising that in certain contexts, we overeat to get certain amount of dopamine release. It’s acting through this same circuit. It has other components obviously, but it’s the same circuit that cocaine and heroine and other drugs of advice hijack. It comes back to the circuit and functioning of circuits in the brain.
Dr. Lisa Belisle: Really, you could become technically addicted to anything that’s going to give you pleasure by doing it. People can become addicted to say, yoga or meditation or good things that are actually good for them.
Vivek Kumar: Absolutely. This is one of the treatments for addiction. We wean someone off of a negative lifestyle, and you get them onto a positive lifestyle. You can feed the reward circuit with exercise. That releases endorphins and dopamine also. You can feed it with social interaction. When I meet you and I meet other people, that feels good. This has been in kids for instance, who are struggling with anxiety and impulsivity and these four traits I mentioned, one of the things that you coach them to do is actually how to interact well and you get them on exercise, you get them into organized sports. You feed that circuit with a completely different set of activities.
Dr. Lisa Belisle: Do you have any final thoughts for us, Dr. Chesler?
Elissa Chesler: Final thoughts?
Dr. Lisa Belisle: How about some interim thoughts? How about that?
Elissa Chesler: At this stage. I think we’ve really touched on the issues that there’s a lot of interconnectivity between normal behaviors, pleasurable experiences, and this a very unfortunate condition of addiction. Unraveling that complexity and understanding how we can get people on a better path is very important. I think the other thing is just getting that care widely available in our communities. There are places in Maine where there may be one or no people that are experienced and certified in this area, just making sure that care is available.
And that preventive measures are available, that’s so crucial right now. We’re going to learn a lot about the biology, but we’ve got to get it out to people.
Dr. Lisa Belisle: What about you, Dr. Kumar?
Vivek Kumar: I think one of the main things we as addiction researchers need to get across about our work is that addiction is not a moral personal failure. It really is a disease. It’s a disease like diabetes, like hypertension. We need to treat it like that. It can be managed. When someone has a substance use disorder or is an addict, we’re not going to cure them, we can manage their illness. Part of that management is that they’re going to relapse, just like someone with diabetes will eventually relapse and their blood sugar will go out of control. It’s very important to get that point across and not judge people who are suffering with addiction and who are dealing with addiction.
Dr. Lisa Belisle: I’ve been speaking with Dr. Elissa Chesler and Dr. Vivek Kumar from the Jackson Laboratory up in Bar Harbor. Mount Desert Island, I guess, technically. I really appreciate the time that you are taking, not only to be having this conversation with me, but also to be working on this because this is something that’s important to all of us, really, in not only in the state of Maine, but around the country. Thank you for all of this.
Elissa Chesler: Thank you.
Vivek Kumar: Thank you for covering this important topic.