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Today on The Fundamentals, our guest is Dr. Jessica Anand, a research assistant professor in the Department of Pharmacology at the University of Michigan Medical School, and a co-chair of the Pharmacology's Diversity, Equity and Inclusion Committee. Her work focuses on developing new molecules to treat different medical needs, like pain with reduced addiction risk, overdose, and potentially mood problems like anxiety and depression. Currently, the main thrust of her research is developing new overdose medications. 

You can learn more about the work Dr. Anand's lab is doing by visiting their website, and you can follow the University of Michigan Department of Pharmacology @UMichPharmacology.

Resources

• Find out more about the research stories mentioned at the top of the show at the links below:
  • Molecule known to slow inflammation linked to scleroderma, could be treatment target
    A variation of the molecule can contribute to fibrosis and scleroderma
  • Did FDA regulation reduce high rates of opioid-acetaminophen overdoses?
    Hepatologists examine data around a 2011 FDA drug mandate
• Learn more about other exciting research happening at the University of Michigan, by checking out Health Lab, Michigan Medicine's daily online publication featuring news and stories about the future of healthcare.

Transcript

Kelly Malcom:

Welcome to The Fundamentals, a podcast focused on the incredible research and researchers here at Michigan Medicine. I'm your host, Kelly Malcom.

Jordan Goebig:

And I'm Jordan Goebig. In this week's episode, we'll be talking about the science behind new drug development, and learn more about how U-M researchers are using their expertise to develop new medications, including ones designed for people experiencing an overdose.

Kelly Malcom:

I'm a big fan of this discussion, because our guest really explains how basic science, which deals with understanding the fundamentals of how our bodies work, leads to drugs that help keep us healthy.

Jordan Goebig:

So, I got curious about other Michigan Medicine researchers working in this area, and I found an interesting article about the molecule A20, and its possible link to scleroderma. A totally different disease and subject area, but highlighting research of the molecular level felt very on brand for this episode.

Kelly Malcom:

And a study that stuck out to me centered on changes in labeling rules from the Food and Drug Administration, which helped keep people out of the hospital, and avoid potentially deadly liver injury from opioid acetaminophen combination drugs like Vicodin and Percocet.

Jordan Goebig:

We'll provide links to the full articles, and info about our featured guest in the show notes. Now, let's get on to our guest.

Today's guest is Dr. Jess Anand. She is a research assistant professor in the Department of Pharmacology at the University of Michigan Medical School, and a co-chair of the Pharmacology's Diversity, Equity and Inclusion Committee. Her work focuses on developing new molecules to treat different medical needs, like pain with reduced addiction risk, overdose, and potentially mood problems like anxiety and depression. Right now, the current main thrust of her research is developing new overdose medications. Welcome.

Dr. Jess Anand:

Thanks, I appreciate you having me here.

Jordan Goebig:

Yeah, we're so happy to have you here today.

Kelly Malcom:

Yeah, happy to finally meet you in person. We're going to start off with some really basic questions. How did you get into studying opioids?

Dr. Jess Anand:

I have always liked where two different fields meet each other. I actually started with chemistry. I had a really great chemistry teacher in high school. He blew something up for each section, so I thought science was really exciting. It turns out, you're not supposed to have explosions in the lab on a regular basis. While I really enjoyed chemistry, I didn't want to just do chemistry for chemistry's sake. I wanted to use it to address problems in people's lives. Where chemistry and biology interface ended up being really interesting for me, and so my degree is actually in something called medicinal chemistry, which is looking at ways to make new molecules, new drugs to treat some sort of unmet medical need.

In graduate school, I tried out a bunch of different things. I worked in a cancer lab for a little bit, but I was really interested in the brain, and how the brain works, and opioids actually change a lot of different things in how we perceive the world around us. They can change how we feel pain, they can change our mood states, like you mentioned. That can be anything from euphoria, which makes people addicted to things, to the flip side, anxiety or dysphoria, feeling bad. These systems are not essential for life. You can knock them out in an animal, and the animal's just fine, but they do fine tune so many parts of our lives. I thought that was really cool, that we could maybe use these as handles to make people's lives better.

Jordan Goebig:

Really very interesting. As I was diving into your research, and what you study, and before we started recording, I made fun of myself for not being a good chemist, one of the words that jumped out to me when I was looking at what you research was the word "Fentalog." That's not a word I was familiar with, but if you spend any more time than apparently I ever had reading a little bit about fentanyl, you will see that word in the second sentence. I would love for you to explain to me, what is a fentalog, and why it's important to identify and understand them.

Dr. Jess Anand:

Fentalog is just smushing two words together, so it's a fentanyl analog. Fentanyl really refers to one specific molecule, but that molecule has lots of cousins that look a lot like it at the chemical level. If you look at their structures, they look very similar. You can tell they're related, they're a whole family, but they're not exactly the same molecule. We say they are analogs, fentanyl analog becomes fentalog.

Jordan Goebig:

Why is it important to identify those?

Dr. Jess Anand:

In 2017, a lot of the drugs that were found in illegal samples from search and seizure, the Drug Enforcement Agency or law enforcement was finding these mixes of fentalogs, and they weren't technically illegal yet. Only the parent in that family, fentanyl, was illegal, and if you made a tiny change to the structure, the DEA, the Drug Enforcement Agency, hadn't caught up yet, and hadn't declared that they were illegal, too. These compounds were technically not illegal in 2017, but nobody knew what they did. People were just making tiny changes to the structure, and hoping they did the same thing, because it wasn't technically illegal. They could sell them for profit, but no one knew what they were. No one knew what they did. No one knew if they were dangerous, no one knew if they were potentially helpful. No one knew if law enforcement needed to be careful when they were handling them or dealing with them.

What I saw as a need was to find out what they do, and if we can make predictions, like, "We know if we put this thing over here, it does this, so anything that has the same change will probably do the same thing." So we could make predictions about what's safe, or what's potentially useful, or what's dangerous to handle.

Kelly Malcom:

You mentioned that these substances fine tune behaviors. Can you talk a little bit more about that? I think people know, people take opioids to alleviate pain, and sometimes to get high. What are the differences between the drugs that we think about on the street and these substances in the body? I believe there are substances that exist in your body, that act like these drugs.

Dr. Jess Anand:

Yeah, that's true. There are targets in the body that both the neurotransmitters, the things in your body your body makes, and these drugs that people take either for medical reasons, people do take fentanyl and morphine, and if you've ever had your teeth out or had a surgery, maybe you had codeine, they all hit the same target in your body, and that's called a receptor. In this case, they are opioid receptors, there's three of them. Your body has these receptors and then makes neurotransmitters to interact with them normally. I don't personally like running, but some people do, and some people talk about this runner's high, where they're pushing their body really hard, and they're getting in the groove, and they get this good feeling. I've never felt good while running. What you're doing is, your body's releasing endorphins, which are the neurotransmitters that bind to the opioid receptors.

They also happen in other situations. If you are running away from a bear, or something, and you sprain your ankle, you can probably still keep running on that ankle, because your body's like, "You can't deal with the pain right now. You've got to keep going." They're also sometimes released in stressful situations, to sort of help you get through, and they can modulate your mood in other maybe fake scary situations. That rush that people get from skydiving or roller coasters is the same system in your body, or anytime you want to keep doing the same thing. I personally like chocolate cake, and you get a good feeling when you eat it. You want to go eat it again. It's that same system that's telling you, "You can do this, just push through, or it feels kind of good to do this thing."

Jordan Goebig:

Thank you for explaining that. You have, clearly, a wonderful way to describe things that makes sense to me, as somebody who both does enjoy running, and chocolate cake more. No, thank you so much. That was a really great explanation of everything so far. Going back to you explaining fentalogs to me, and an area you study. And thinking about like, we know that these things are bad, and you're studying those, and there are lots of reasons why we need to better understand them, to help the police, and help legislation, and things like that. But there's also that therapeutic side that you mentioned briefly. Is that an area that you're currently studying, and is your lab focused in? I'd love to hear more about that.

Dr. Jess Anand:

To talk a little bit about that, we need to introduce another couple of ideas. I said there are these receptors that are in your body, that both the drugs that you take and those neurotransmitters in your body bind to, and they're like dimmer switches. You can turn them all the way on, and that would give you the maximum pain relief, that would give you the maximum euphoria. That would also give you the maximum respiratory depression. That's actually why they're dangerous, they stop your breathing. You could also turn it on part of the way. You don't have to turn the dial all the way up to 11. You could just turn it on part of the way, and that could be a therapeutic use for the pain relief. We do have people who have chronic pain, that they're suffering every day, and right now, opioids are our gold standard for treating that. If you have some sort of surgery, that is what we give people to help them deal with that pain. So that is a legitimate medical need.

You could turn it on even a smaller part of the way, just a little bit above all the way off, and that could help somebody wean off of drugs if they've started taking them and need them to feel normal. They've become tolerant to it, they need it to feel like they can get through their day, you give them just a little bit, and that will help them step down off of it. That's similar to a nicotine patch, or nicotine gum, to get people to quit smoking, same thing. You can give someone just a little bit to help them stay off of the drugs.

You can also turn that receptor all the way off. That's actually called an antagonist, and that would prevent someone from overdosing. If you have someone who's taken too much, they've turned the dial all the way up, they've stopped breathing, that's dangerous. You can go and give them something that binds to the same exact spot in your body but blocks it instead of turning it on, and that should rescue them, and prevent them from dying. Depending on how we get the chemicals, the molecules to interact with these receptors, you can have different uses for them.

Kelly Malcom:

Would that be something like Narcan?

Dr. Jess Anand:

Exactly.

Kelly Malcom:

Okay.

Dr. Jess Anand:

Yes.

Kelly Malcom:

Okay.

Dr. Jess Anand:

That's actually a really interesting point. I work on fentanyl analogs, and fentanyl is a different family than Narcan is. Narcan's in the same family as heroin, and morphine, and Vicodin, and a lot of the more established drugs. Fentanyl is in its own family, and so we don't have anything that is in the same family as fentanyl that blocks the receptor.

Kelly Malcom:

Oh, interesting.

Dr. Jess Anand:

That's actually something I'm working on developing, hoping that it would be better able to block a fentanyl overdose than Narcan is. Narcan right now wears off really quickly, and sometimes that means that the thing that the person overdosed on is still in their body, even after the Narcan has worn off. That becomes dangerous the second time around, because there's nothing to block that receptor anymore.

Kelly Malcom:

Everyone knows there's an epidemic right now. I'm curious about how the opioid epidemic has affected your work as a chemist. Has it had an effect on what you've decided to study?

Dr. Jess Anand:

Yeah, actually. I started with my graduate work trying to make painkillers that were less addictive. So, something that would treat the pain, and would help people feel better, but wouldn't make them feel so good that they'd want to keep taking it, so the pain relief without that euphoria, that high. Because there is this epidemic, a lot of people are dying. I've actually pivoted, and now I'm looking at rescue treatments, so things that would prevent people from dying. The cause is still complicated. People take drugs for a lot of reasons. Usually, it's because that feels like the best option available to them, and that's a much bigger societal problem. From a chemistry angle, it's a lot easier to be like, "At the very least, we can keep people from dying now, and then work on the societal stuff over time."

Jordan Goebig:

What has been the biggest surprise you've encountered through your work about the way that the body responds to opioids?

Dr. Jess Anand:

The biggest surprise? The body is amazing. It does all kinds of wild stuff. I think part of it is, your body adapts to what you give it. Something on day one will not be the same as taking it every day for a year, a lot of the time. We don't really know a lot about... everyone's different. How about that? If we both start with the same dose, and take the same dose every day for a year, at the end of that year, we might be in different spots, and we don't really know a lot about why. It's not just that one receptor that I was talking about, where the drug interacts with your body, because there's lots of stuff in your body. Your liver breaks things down so that you don't have toxins build up in your body, and your body and your liver and my liver are probably different.

There's this layer between my brain and the rest of the body that protects it, because your brain is delicate. The layer between my brain and the rest of my body, and yours, is maybe different. This variation is just wild.

Jordan Goebig:

We hear a lot, from having people in here, about that need for the personalization of medicine and therapeutics in many areas. It sounds like there is that similar thing going on in your field as well.

Dr. Jess Anand:

Yeah, exactly. The hard part is, if you're in an emergency situation, you're in an ambulance, I've got to make a decision right now. What do we offer people that will work for the most number of people right now? We don't have time to be like, "Can I just analyze your genome real quick? Just hold on."

Jordan Goebig:

Yeah, this isn't like the sci-fi movie, "Us." "Let me put this in a little box." Very interesting.

Kelly Malcom:

I know you said you're looking at rescue treatments for fentanyl. How long does it really take to go from the basic science, which you do, to an eventual treatment like that?

Dr. Jess Anand:

If you're starting all the way from an idea, so I had an idea, maybe I don't have anything other than an idea, I've just got this little dream, that can take quite a while. That can take 15, 20 years. I'm a little farther down the pipeline than that. I have what's called a hit. I have something that meets many of the criteria that we're interested in, but maybe not all of them. Some of them are scientific concerns. Does it target the right receptor in your body? Does it target the right thing? Does it do the right thing at that receptor? Does it actually block it, as opposed to turning it all the way on? I've got something that does that. But then, you remember how I said, your liver breaks things down? Can it escape the liver long enough to do its job, or will the liver break it immediately, and then it's gone from your body?

Those are all scientific concerns. Pharmacodynamics is a word I'm going to introduce, that's what it does at the receptor, and pharmacokinetics is the rest of it. Does it get to the right place in your body? Does it get metabolized? Does it get broken down? Does it get eliminated from your body rapidly? That's one set of concerns. The other set of concerns is all regulatory stuff. Will the FDA approve it? Do you have a packet that shows that it is not only efficacious, it does its job, but it's safe, it won't hurt the patients?

One of, I think, the most frustrating concerns is intellectual property. I could have the perfect molecule that does exactly what I want to, but if it's not patentable, a company's not going to invest in it. I am just an academic lab, so I don't have the capital, I don't have the money to do all of these large clinical trials, and get something to market, and then sell it to patients. I can't make millions and millions of doses. I need someone to buy this molecule from me. If it's not patentable, it won't be profitable, and if it's not profitable, no one's going to buy the idea. I think that is one of the most frustrating hurdles in getting a drug to market, that it needs to be commercially viable, not just do its job.

Kelly Malcom:

That's where it's good to work at a place like U of M, that is investing in opioid research.

Jordan Goebig:

How long have you been at the university?

Dr. Jess Anand:

That's a complicated question. I actually did my graduate work here. I was a PhD student in med chem first, and then I postdoc'd in pharmacology, and I went to the other end of the spectrum. I did what's called behavioral pharmacology, where I checked in living organisms whether or not molecules work. Now, I'm in this between space, in vitro pharmacology. I started as a student in 2007.

Jordan Goebig:

Oh, wow.

Dr. Jess Anand:

I've been here a while.

Jordan Goebig:

Very cool. You're a good person to ask for recs. As somebody who's been here for a while, and you're working on these things, and you're talking about these hurdles, what are the benefits to being at the University of Michigan, to help you overcome those hurdles? Are there collaborators here that are doing this with you?

Dr. Jess Anand:

Yes. The University of Michigan has a huge population of people that do opioid research. Remember, I was talking about those neurotransmitters your bodies make. One of those groups is called the enkephalins. The woman who discovered those is actually here at the University of Michigan. There are a lot of people who do a lot of different kinds of research, both on drugs of abuse and opioids in particular. There are a lot of people to go talk to. I'm at the Edward F. Domino Research Center. I can go down the hall and I can knock on somebody's door, and I can say, "Hey, Dr. Levitt, you specialize in breathing. I've got this really weird question about respiratory depression." I can go talk to somebody else who's a chemist, who's ex-Pfizer, say. I can go knock on his door and say, "Hey, I've got a really weird patent question, because you used to work in industry. So there are a lot of great minds here.

The facilities are also really good. We have a lot of cores here at U of M, where I don't have to learn every single technique in the world. I can just go talk to the people that make vectors, and say, "Hey, can you make me a vector? Hey, can you make me a cell line?" I don't have to figure it out myself. I can have the idea, and then go work with somebody.

Jordan Goebig:

I've been at the university longer than six weeks, but I've only landed here, and I feel like I've heard that a lot, in not a cheesy way. Collaboration is a real word that's not just lightly thrown around here, and it's nice.

Dr. Jess Anand:

It's really nice, because not everywhere is as collegial as we are here. People do genuinely want to collaborate. It's not a super competitive environment, which I appreciate.

Jordan Goebig:

Yeah. Are there any specific projects or publications that you have coming up, any people that have just been instrumental to your time here that you want to talk about, or give a shout-out to?

Dr. Jess Anand:

My faculty mentor, Dr. John Traynor, he's actually the director of the Domino Center, and he's been great. He's pulled a lot of people in who work on either CNS, central nervous system, so brain stuff, or opioids in particular. He's put together a really great group, so that's made it really easy to go find someone who has more expertise in the thing, or I get to be the expert sometimes, and people come knock on my door. It's really nice that we have this group.

Kelly Malcom:

So, as a basic scientist, what do you feel is basic science's role in addressing the opioid epidemic?

Dr. Jess Anand:

Basic Science is the foundation for everything. It's not flashy, we're over here in the corner, asking why, poking it with a stick, trying to figure out, how do brains work? How do receptors work? How do bodies work? This feeds into the question about how long it takes to get a drug to market. It takes a really long time. A lot of times, when you think about new medications, you think about your doctor or your pharmacist or an EMT; someone actually giving a medication to a person in need, and that's important. The social end of things, supporting people so they can take their medications, and they can take them on the schedule they're supposed to, those are all important things, but that glosses over the fact that somebody had to discover that medication, and figure out what it did in your body, and how it worked.

That's not the flashy end. People like to see doctors in white coats rushing in and saving the day, and saving someone's life. That's not possible without the basic research. Sometimes, it's hard to translate how basic research gets you to that end flashy point, where you save someone's life with a white lab coat and a hero's cape. I do wish that there were a clearer way to explain this. This is also partly on us as basic scientists, that we have to explain why we're doing what we're doing.

My favorite example of not doing a good job of explaining why you're doing what you're doing is, there was a congresswoman few years ago who was very upset. Her son had a rare disease, and she was really frustrated that this lab was getting federal money to study fruit flies, when they could be studying something to save her son. This is where we as basic scientists fell down. You can't make this up, the lab that she picked was studying genetics, and they were actually studying the gene that causes that rare disease in humans in fruit flies. We can't ethically take human children and change their genes, that's not ethical, but we can take fruit flies and change their genes, and see what happens. It makes a very similar disease, and then we can see, "If we give them these drugs, does it alleviate that? Does it make the fruit flies better," and then you can go from there.

That means that we, as basic scientists, are not doing an adequate job communicating why we're doing what we're doing. I'm not just in the basement, having fun, I'm trying to actually figure out, they're called structure activity relationships. I'm trying to see, if I change the structure of this molecule, do I change its activity? Instead of turning that light switch all the way on, can I turn it off, so it blocks it, and save somebody's life? Can I turn it part of the way on to help somebody get clean, so they're not going into withdrawal, they can get their life back? Can I dial this up and down in a way which, if I explained it badly, I'd be like, "I don't know? I make a bunch of molecules, and I see what they do." That's not going to get anybody engaged. We have to explain that this is the basics for what everything else is built on, and there's a lot of "failures." There's a lot of things that don't do what we expect them to, but we can learn from it, to do better next time.

Jordan Goebig:

This is a good segue into my next question, because you're really fantastic at providing examples that are very visual for someone like me, who needs those sorts of things. You've also introduced a couple of new words to me today, so I appreciate that you're expanding my vocabulary. I truly do appreciate that. I'd love to know, do you teach at all, or mentor?

Dr. Jess Anand:

Yeah, I do some formal teaching. Right now, I teach a few sections of our graduate program in pharmacology. We have an introductory course, it's called 601, and it's the class that everybody has to take. I teach a couple of sections in that, and I do teach a little bit of our grant writing course for our graduate students, so that they can get funding to do their research. I also do a lot of informal teaching. I do a lot of mentoring in the lab. I have a good-sized group of undergraduates. I think right now, I've got six undergrads in the lab with me, a couple of techs, and some graduate students as well. And that's a lot less formal. I’m at the bench, I'm helping them work through how to design an experiment, how to interpret their results. If you forget your controls, did it not work because the drug doesn't do anything, or did it not work because you messed something else up, and nothing worked? Working through that process of making sure that we're doing the science correctly, and that they can plan things out. I do a lot of that.

Kelly Malcom:

Mentoring is so important for young scientists, and I definitely want to touch on your work as a co-chair of the diversity, equity and inclusion committee for pharmacology. What does that really mean, and why is it so important that we increase diversity, and equity and inclusion?

Dr. Jess Anand:

We like to think of science as something super cut and dried, where there's only one right answer, right? And it's not. It's like the parable of the people with the blindfolds and the elephant. There's a bunch of blindfolded people, and one person finds the tail, and they're like, "An elephant is like a rope." Someone else finds the side, and, "An elephant's like a wall." They find the leg, "An elephant's like a tree." We're all poking around in nature, trying to figure out what it does, because all of this stuff is too small to see. You can't really open up somebody's brain, and look at the little receptors in there.

The perspective we bring to problem solving, and thinking, and putting things together changes how we interpret the little facts that we have. An elephant isn't a rope, or a wall, or a tree, it's an elephant, but you have to put all these pieces together to get the whole picture. You can do that with a diversity of techniques. You can ask the question in different ways, but a lot of it also relies on the scientists themselves. How do they think about things? That can be diversity in training, or just diversity in background. People are all different, and they all think about things differently. The more different minds you have in the room, the more likely you are to get different parts of the picture. Making sure that we can give everyone the opportunity... not everyone has to do science. It's okay if you're like, "This is not my jam. I want to go do something else," but I want everyone to have the opportunity to come and do science if they want to. Supporting that in the Department of Pharmacology includes making people feel like they are welcome, and seen.

People are not just their identities, but it helps if you feel like you can be safe and comfortable enough in a space to ask those questions that might lead to an entirely different way of thinking about something, or to throw out that harebrained idea that might be garbage, or might be a solution. You need to be safe enough and secure enough in yourself to do that, because asking questions can make you look dumb. You have to be confident and safe enough in yourself to be like, "It's okay. Maybe it's dumb, or maybe it's amazing. We won't know until we explore it." That's part of why I want to make sure that we make our trainees and our employees feel safe in the department, to do that job.

Jordan Goebig:

I'm in awe of you. I'm very impressed, and I'm just so appreciative of all the things that you've taught me today. I am one of those people who did not do great in chemistry. Science wasn't something that I knew I was going to excel in, but I feel like hearing from you is one of the reasons I call myself a lifelong learner in one of our intros. It's because you make things interesting, and you make things easy to understand. I have a daughter, and I look to you and everybody, people doing all types of things, as being her future role models when she's not 18 months old, and just destroying our house. I really appreciate that she can listen to this in 10 years and make fun of me, but also learn something from you. Thank you so much for being here today.

Dr. Jess Anand:

It's been a pleasure. Thank you for having me.

Kelly Malcom:

Thanks for listening. The Fundamentals is part of the Michigan Medicine Podcast Network, and produced by the Michigan Medicine Department of Communication, in partnership with the University of Michigan Medical School. Find us and subscribe wherever you get your podcasts.