说话人 1: Welcome to the Salk Institute’s podcast, Where Cures Begin, where scientists talk about breakthrough discoveries, with your hosts, Allie Akmal, and Brittany Fair.

Brittany Fair: I’m here with Dr. Eiman Azim. Dr. Azim investigates neural circuits in the spinal cord and brain to find out how skilled movements work, in particular, goal-directed actions like catching a ball or throwing a dart. He has identified two genetically distinct spinal circuits crucial to these actions. One class of neurons, responsible for the stability of a limb during movement, and the other, responsible for providing rapid feedback to help the brain monitor and correct movements. Welcome to Where Cures Begin, Dr. Azim. Do you want to tell me a little bit about what you’re working on here at Salk?

Eiman Azim: Well my lab is interested in how the brain controls behavior. Ultimately when you think about behavior, it’s movement. You have to get your muscles to contract to move, whether you’re eating, breathing, reaching for your water. And so, what we try to do is investigate how neural circuits in the brain and spinal cord control different types of movement. In particular, we really like dexterous movements of your arms and your hands, and your fingers.

Brittany Fair: So they’re very complex movements?

Eiman Azim: Yeah. And if you think about these dexterous movements, it’s not just musicians and athletes that impress us every day, but it’s all of us. I think we should all be pretty proud of ourselves. We can button our shirts. We can type emails. We can coordinate the contraction of dozens of muscles with pretty amazing speed and precision. And the problem is, we have not a very clear understanding of how the nervous system is able to coordinate such complex behaviors.

Brittany Fair: Interesting. So, if I hold a pen and I write, we don’t actually know how our brain controls that movement?

Eiman Azim: I’d say in large part, no. In very large part, no. We have an idea of different regions in the brain and different circuits that are important. So for example, if there’s a neurodegenerative disease or injury that takes a part of the brain out of the system, we know that these types of dexterous behaviors are very vulnerable to that injury or that disease. But, a deeper understanding of how in the functioning system, all of these of these neural circuits interact and communicate to coordinate such behavior is mostly lacking. And so what we’re trying to do is use sophisticated molecular genetic tools to get into the nervous system and figure out what all the pieces are, and figure out how they work together.

Brittany Fair: Sure. And what are some of those tools that you mentioned?

Eiman Azim: Yeah. So over the past few decades there’s been this amazing, molecular genetic revolution in neuroscience. Essentially what that means is it lets us take advantage of the fact that for example, that different types of cells including neurons express different genes. That’s how they become distinct from each other. So if we can understand those molecular codes, then we can get access to those neurons and gain the specificity we need to go in and look at how these neurons connect to each other.

Or, in some experiments we can go in and we can take those particular neurons out of the circuit completely, or turn them on or off at will and really try to investigate their function. In the past, a traditional approach has really lacked that selectivity. You really could only go in and make a big lesion or inject a drug, which is fairly non-specific when you consider that there are hundreds or thousands of different kinds of neurons all intermingled in every part of the brain. And so what molecular genetics allows us to do is go in and sort of disentangle that with surgical precision.

Brittany Fair: Okay. And could this type of precision allow you to create a treatment or lead to a cure for a neurodegenerative disease or a spinal cord injury?

Eiman Azim: I think there is a very large number of implications of this kind of research. What I fundamentally believe is that, if we want to develop better approaches to diagnose and treat disease and injury, we need a much better understanding of how the normal system fundamentally operates. So my lab in large part tries to get to this fundamental basic-science understanding of how the motor system works.

Brittany Fair: The Azim Lab hopes this fundamental research will provide them with a better understanding of diseases such as Parkinson’s Disease. Parkinson’s Disease is a disorder of the central nervous system that affects the neurons that produce the neurotransmitter, dopamine. Patients often experience issues with movement or resting tremors. And currently, there is no cure for Parkinson’s.

Eiman Azim: If we have better basic-science understanding we’re going to have a greater foundation from which to build cures.

Brittany Fair: It sounds like you have this very large puzzle and you’re trying to figure out not only what are the pieces in the puzzle, but also how they each fit together.

Eiman Azim: Exactly, yeah. And not just how they fit together in a static picture, which is how they connect to each other, but dynamically how they fit together. Throughout a movement, how does a communication of these neural circuits with each other change in order to coordinate these behaviors? So, what most of the projects in my lab are looking at from a 30,000 foot view is the interaction of the motor command outputs that get you to move, and all the feedback that comes flooding back into your system, from your muscles, from your skin, from your eyes. Those two pathways are constantly interacting in a very dynamic way. And we don’t have a very good understanding of how that interaction underlies the really rapid coordination of precise movements.

Brittany Fair: Okay, so you have signals coming from your brain and going out to your muscles. And then you have sensory input that’s coming in from the environment. And these signals are traveling back up to the brain, is that correct?

Eiman Azim: Yeah, exactly. And the interaction between those two very generic forms of information is not very well understood. But we do know that each part of that is critical for coordinated movement. Things get very complicated. One of the big projects in my lab right now is looking at how you control the strength of that feedback, sort of with a volume knob turning up or down what we call the gain of that feedback. You can’t just allow all the feedback from your body to come in unfiltered, we’d be completely overwhelmed. A lot of that feedback is noisy or disruptive. And so we’ve been looking at circuits in the brain that, again, in a dynamic way, as you move, can turn up the strength of the feedback that’s really salient and important for movement, and other circuits that will turn down the strength of the feedback that’s disruptive or noisy.

Brittany Fair: That’s funny. I imagine a tiny little deejay inside your brain-

Eiman Azim: Exactly-

Brittany Fair: … deciding what’s going to go out and be played.

Eiman Azim: Many deejays, that’s the problem.

Brittany Fair: I see.
Growing up, did you always know you wanted to become a neuroscientist?

Eiman Azim: No. I always loved science. When I was a kid I was really into space, and I was really into dinosaurs. So I was really interested in the idea of studying a specific topic and becoming expert at it. But it really wasn’t until college that I fell in love with neuroscience. So I was really passionate about philosophy when I was at Stanford as an undergraduate. So I was majoring in philosophy, and I was also majoring in biology. But philosophy was really my passion for the first couple years of college. And then, I got a bit frustrated that while the questions are grand and fascinating, there were not a lot of good ways to come up with definitive answers. And so that’s when I decided I want to enter a laboratory science and try to see if we can get access to some of these questions, and collect some data that could point us in the right direction.

Brittany Fair: Yeah, and philosophy’s an extremely difficult subject to study and really lays the groundwork to how we approach science. Do you feel like having a background in philosophy has prepared you for your current career in research?

Eiman Azim: I do. I think philosophy teaches you how to think about a problem. We’re all philosophers. We have doctorates in philosophy. For some reason, the common definition of philosophy has gotten smaller over the centuries. But I really view what we do as still an aspect of philosophy. We’re looking at the world. We’re curious about a problem. We try to come up with rational and intelligent ways to try to address that problem. And that applies across life sciences, across the sciences in general.

Brittany Fair: Absolutely.
And when you went to graduate school at Harvard, and then you were a post-doc fellow at Columbia. These places are both very far away on the East Coast. What drew you across the country to Salk?

Eiman Azim: Oh, well, I grew up in Colorado which shares a lot of the vibe that California has. And then after going to the Bay Area for college, I just fell in love with California. So I always knew I wanted to come back. I loved being in New York and being in Boston for those 10, 11 years. But I was pretty certain that I was going to come back. In fact when I made a list when I was still a post-doc of all the jobs I wanted to apply to, and I rank ordered them as what would be my favorite, I unintentionally had the top seven schools I listed were all in California. So I think it was a sign I should come back.

Brittany Fair: That’s completely fair. There’s no place in the world like California.

Eiman Azim: That’s California. But the Salk was really special. It was different than any other place I was looking. It’s small by design. It’s incredibly collaborative. There’s no departments. There’s very few barriers or boundaries between disciplines. There’s a lot of advantages to a big university with large departments and neighboring hospitals. But they don’t have the atmosphere at Salk where when you’re walking to lunch or walking to get your coffee, you’re running into one of the best plant biologists in the world, and you just strike up a conversation. That just doesn’t happen very easily at big universities.

Brittany Fair: Do you find yourself able to collaborate with people outside of your specific focus at Salk?

Eiman Azim: I definitely have a lot of great discussions and collaborations ongoing at Salk. So, one example is, my lab’s working with Sam Pfaff and Axel Nimmerjahn’s labs to develop new approaches for trying to record the activity of the spinal cord. So, if we want to understand how the brain works, one of the major tools that we need is an ability to record the activity of neurons as the animal is behaving.

So we can correlate the activity of the brain to behavior. The spinal cord is a really tough place to do that because it moves around a lot when the animal is moving. And so that’s been one of the least accessible parts of the nervous system if we’re using a lot of these modern approaches for recording neural activity. So that’s one collaboration.

I interact constantly with Kenta Asahina, my neighbor. We do joint lab meetings. They work on drosophila as a model system, looking at aggression and social interaction.

Brittany Fair: And that’s a fly, right?

Eiman Azim: That’s a fly, sorry. And the great thing is, we’re both fundamentally fascinated by how the brain controls behavior. But we use very different tools and model species to address those questions. So I think Kenta and I, and our labs gain a lot by seeing what the other lab is working on each week and trading ideas.

Brittany Fair: Absolutely.
So, you are now faculty at the Salk Institute. Do you have any advice for aspiring neuroscientists?

Eiman Azim: Science is an amazingly fun and amazingly difficult job. So the only way it works is to make sure that the questions you’re asking fascinate you. I’ve seen a lot of people who sort of burned out on the idea of science and all the late nights and failed experiments, because in the end, the experiments they were doing didn’t fundamentally fascinate them. So I tell all of my students and undergraduates in the lab and everybody, that the number one most important thing is to have the drive and the curiosity, and the passion for your question. Some questions are going to interest you more than others. So really follow your passion first and foremost.

Brittany Fair: What do you think the future holds for understanding the neural basis of movement?

Eiman Azim: I think we’re at a really fascinating and fundamental moment in neuroscience in general, but especially in motor control. So, as I started out saying, we really want to understand how the brain controls behavior. And movement is the way, it’s the output. And so I think it’s the most accessible and quantifiable part of these really complex circuits. And the field is already gaining these amazing insights that are not only telling us how our nervous system might be working, and also telling us what might go wrong in disease and injury, but people have been using that information to inform the development of therapies and prosthetics.

I mentioned earlier, your output is interacting with your feedback. So there’s amazing new research in prosthetics that is not only giving the ability of people who, for example, have spinal cord injury to control a robotic limb, or to control a prosthetic arm, but also to have that arm give feedback back to the brain so that this person can interact with the world more. And the way that you develop those things is by using the lessons we’ve learned in the laboratory.

Brittany Fair: Sure. How many years off do you think that is, realistically?

Eiman Azim: In some ways it’s already happening and it’s only going to get better. To get to the level that we all imagine and that you would see in the movies, I think is going to be a little while. Everything’s incremental and for patients who need help now there’s already things that are very exciting that are happening.

Brittany Fair: It may seem impossible, but Dr. Azim is able to balance his full-time research career while being a husband and a new dad. Pretty much, he’s a super hero.

Eiman Azim: Balance is a strong word. We’re making do. Yeah, my wife, she’s a neurosurgeon at UCSD. And we first met right when she’d finished medical school. Actually, she came here to UCSD for medical school. And I was at Harvard for my PhD, studying for my PhD. And she came and did an internship at MGH, where my lab was. And we shared a floor, and we shared a lunch room, and most importantly, the coffee maker where I was usually stationed. And that’s where we met and hit it off. And then soon after, she went to New York for her residency, and I followed a couple years later after I finished my PhD.

Brittany Fair:That’s fantastic. And she was able to come here when you trained at Salk?

Eiman Azim: Yeah. She finished her residency about the same time I was finishing my postdoc. So timing worked out really well. And then we went on a job market that’s really tough just for one person.

Brittany Fair: This is an understatement. It can be nearly impossible, but they somehow made it work, a neuroscientist and a neurosurgeon, both employed in one of the most competitive job markets in the world, San Diego. Do you both ever collaborate together?

Eiman Azim: Yeah. Well we have a couple collaborations in the works. So one is a submitted grant where we’re looking at how we can improve deep-brain stimulation therapy for Parkinsonian patients, using some of the motion tracking technology that we’ve been working with in my lab. And another is, she has this amazing access that very few people have to the human brain. So she treats epilepsy patients. And when a subset of patients who are candidates for surgery go into the OR, what she does is she implants electrodes, either on the surface of the brain or internally in the brain. And then those patients will be there for a week or two.

And the goal is to have a seizure occur so you can find the focus of that seizure, and later go in and maybe reset that tissue. But while they’re in there, for a week or two, you have electrophysiological or the recording access to the human brain. Which is very rare and very exciting. So we’ve been thinking up cool questions that we can ask while those patients are in there and are willing to play little video games that we give them. We’re really grateful for their time. And I think often they’re really excited to be part of our work.

Brittany Fair: And now, you both have a baby.

Eiman Azim: We do, yeah, four months old.

Brittany Fair: Four months old, is it a boy or a girl?

Eiman Azim: Boy. His name is Elian.

Brittany Fair: Wow. And what is it like having a baby while being a full-time assistant professor?

Eiman Azim: I’m still figuring that out. But it’s a balancing act. I got this advice from a friend of mine who was a mentor of mine when I was in grad school. And he had a child when he was a postdoc. He said you basically have to get the same amount done in a lot less time. And so I’ve really tried to focus on cutting out all of the extraneous stuff so I can just get my science done, and go home and play with my son.

Brittany Fair: Is sleep considered extraneous?

Eiman Azim: Often. Yeah, I’d say sleep has suffered.

Brittany Fair: Understandable.

You’re really balancing not only research, too, but mentoring. How do you fit in mentoring with all of these other commitments?

Eiman Azim: Yeah, mentoring is a fundamental part of the laboratory experience. I had amazing mentors. And I learned a lot about the meaning of mentorship. So science isn’t just doing insightful experiments and publishing your data. It’s about training the next generation of scientists. And I think that’s incredibly important.

So I meet with everybody in my lab on a weekly basis. And of course we discuss the science. But we also discuss, “What do you want to do next? How do we get you to where you want to go? How do you communicate your science more clearly to the public so you can advance in this career?” And so I think it’s a fundamental part, sort of inseparable.

Brittany Fair: And I have to ask. You study how the nervous system controls movements. Are you excited to watch your child grow and start to reach these developmental milestones such as reaching and grasping and walking?

Eiman Azim: Oh, absolutely. It’s been fascinating. He just rolled for the first time about a week ago. Which was just amazing to watch. What’s really great is that he, and babies in general, are amazing experimentalists. They try something and then it works or produces an outcome. And they do it again and again to confirm that it’s true. And if something fails they’ll go and try something new. We have this toy that he has to spin and it only spins one way. So once he figured it out he had to be rigorous, and did the experiment at least 10, 15, 20 times.

Brittany Fair: Of course.

Eiman Azim: Until we had to move him on to the next toy. But it’s been really, really fun to watch so far.

Brittany Fair: That’s great. And he’s four months old. So he’s rolling. So he’ll start to maybe sit up in the next month or so.

Eiman Azim: Yeah. And then we’ll get him in the lab.

Brittany Fair: Of course.

And if for some reason, you woke up tomorrow and you were no longer allowed to be a neuroscientist, for whatever reason, what career would you have?

Eiman Azim: That’s tough. Of course I already mentioned philosophy which fascinates me. But, to be honest, I love music. I’ve been in a few bands. And while I don’t think I would be happy without the fulfillment of something like science, it’s a lot of fun to be up on a stage playing with your friends, playing music you wrote. So who knows? Maybe I would have followed that path.

Brittany Fair: What do you play?

Eiman Azim: Guitar.

Brittany Fair: What kind of music is it?

Eiman Azim: It’s rock. It’s a good eclectic mix of things. It’s been a little while. I was in one band in college, and then when I was a postdoc in New York I was in a band and recording an album. So I’m yet to find the time or the band mates here in San Diego but it’s on the back burner for now.

Brittany Fair: Do you have any recordings?

Eiman Azim: I do, but I’m not going to tell you where they are.

Brittany Fair: Thank you so much for joining us today, Dr. Azim.

Eiman Azim: You’re welcome.

Brittany Fair: That’s it for today. Join us next time for more cutting-edge Salk science.
The music for our production today was found on the deep, dark web. The bands include The Killing Phantoms and Melt On, Friend. Two bands where Dr. Azim may or may not perform on the guitar and sing vocals.