Member Spotlight: Dr. Paul S. Larson

Dr. Paul S. Larson is a Professor of Neurosurgery at the University of Arizona-Tucson and the Chief of Neurosurgery at the Southern Arizona VA Health Care System. He has fostered various innovations in neurosurgical technology and techniques and has led multiple clinical trials with a focus on stem cell and gene therapies for treatment of different movement disorders, including Parkinson’s disease.

He grew up in Arizona and obtained his medical degree at the University of Arizona College of Medicine-Tucson. He completed neurosurgery training at the University of Louisville. Subsequently, he joined the neurosurgery department at the University of California at San Francisco for the next two decades before returning to Tucson in 2021. 

Apart from being a busy functional neurosurgeon and devoted teacher/educator, he is a model clinician scientist. Read on to gain insights on inspiring pioneers and mentors, how a successful career is made in three phases, and having patience and persistence are two qualities to build a successful career in functional neurosurgery.  

1) What was your initial inspiration to go into medicine and then move toward neurosurgery as a specialty? 

My interest in pursuing medicine was there since childhood. I always just thought I would want to be a surgeon. I think part of the motivation was the show MASH, because we used to watch that when I was growing up, and in fact, I thought about becoming a trauma surgeon at first.

The neurosurgery interest didn’t happen until I had to take a particular elective in my last year of undergrad. I took a neuroscience course, and that really changed my direction with medicine. 

2) What drove you to functional neurosurgery? 

The neuroscience element led me to get very interested in research. I started an MD/PhD program, since that was a big thing back then. In the process I got connected with someone who was doing motor systems work. We were looking at cerebellar role in motor learning and locomotion; and at the time, there was a neurologist at the University of Arizona who became a very famous movement disorders neurologist, Dr. Erwin Montgomery. 

We used to admit Parkinson’s patients to the hospital to tune up their meds for a week at a time, and I started shadowing him. That got me further interested in movement disorders. It was a nice marriage of basic science and clinical application. 

3) Who were some key mentors in your career? 

Definitely, Dr. Erwin Montgomery was a very early mentor for me. He opened my eyes to how you can have a very meaningful impact on movement disorders patients, for example. Then in training, I had several mentors. For instance, Dr. Henry Garretson was the chair of my department when I started, and then Dr. Chris Shields became the chair during the middle of my training. They taught me a lot about work ethic and what it really means to be a good clinician and a clinician scientist. 

My first job out of training was at UCSF, and Dr. Mitch Berger, the chair at the time, was very influential on the way I just think about building one’s career. And Dr. Phil Starr, who was my partner but also a tremendous mentor taught me a lot about how to think about science, how to run a research enterprise, how to take care of patients, and how to teach. Dr. Krystof Bankiewicz, a basic scientist in our department, was an important mentor. He had a huge influence in the way I think about cell delivery, and about gene therapy delivery. So, it’s been a lot of people over the years. 

4) As you were a key member of the team that developed the Clearpoint navigation system, can you talk a little bit about that process leading up to it? How did you collaborate with industry and other partners? 

I remember this very well. I remember standing on the deck of my house in Kentucky as a chief resident talking to Phil about this in 2000. Phil and I had both trained at places where they were early adopters of intraoperative MR. Phil trained at the Brigham, where they had a big program there; and at University of Louisville, they had the third intraoperative MR. It was really our two centers that were doing this, and it was being used to take brain tumors out. I remember this very early conversation before I even got hired at UCSF. We started talking about the idea that if MR is good for taking things out of the head, maybe it’s good for putting things in the head. 

So, it was really the two of us, and the third part of that was Dr. Alastair Martin, who was an imaging scientist. It started as just an idea, and Alastair had the imaging chops, while Phil and I had the stereotaxy chops. For many years, it was just a “weird” thing that we were doing in San Francisco. Everyone was interested in it, and people came and watched it. But you couldn’t do it unless you had Alastair Martin sitting down and running your scanner to make it do what it needed to do. 

Initially, the work was funded by various industry members. Medtronic funded it for a while, but no one was really interested in taking it to the next level because asleep surgery was very controversial at that time, so no one really believed that it was going to be a thing. Eventually, I presented some of our early results at an ASSFN meeting, and the CEO of the company that would become Clearpoint was in the audience and heard the talk. That was the start of a relationship that led to them getting FDA approval in 2010 and the rest is history. 

5) Along this theme of innovation, how do you feel your career evolved over time in terms of the research/academic aspects? Any lessons learned?

In the beginning, I was trying to be a transplant basic scientist as my interest was cell transplantation. I had what I thought was a pretty good idea – and still think it’s a good idea – of how to help train grafts into a motor circuit. I had a rodent lab, and I was trying to run a VA hospital service and then be a basic science person at night. That’s not a great formula for success. I did hire some lab people to help run things, and I wasn’t very smart or savvy about who to hire, so that initially didn’t go well. 

Then, we got involved in being a site for a clinical trial. We had a basic scientist in our department named Dr. Krystof Bankiewicz. We were collaborating to translate some of his work to the clinic. I realized that was much more my forte – helping figure out how to best get these treatments in the head. One thing led to another, and we happened to be in the right place at the right time. We got more involved in that kind of delivery work. Krys is a trained neurosurgeon himself, but he was very influential in partnering with industry. We’re in a specialty that’s very dependent on industry. We’re device-based, and we’re becoming increasingly biologics-based. While there are people doing their own devices and their own biologics, most of this is through sponsors. Many are small companies that need help translating the science into the clinic. So, industry is a very vital partnership with our specialty, and I think a lot of people don’t recognize it as such. 

6) That is an insightful comment about industry. Often in medicine we’re told to be wary of industry and that their interests may not align with physicians and patients. 

I think a lot of us were trained to believe that the industry are the bad guys. They’re trying to sell you a screw, or they’re trying to sell you a rod, etc. And I think in functional neurosurgery, we are dependent on device companies. We’ve all seen examples where they’ve not gotten things right. We’ve all seen decisions that were made or designs of a widget that we use, where you can just tell there wasn’t a surgeon within 100 miles of the design of that thing. In fact, I think we really need to be more collaborative with industry. It’s not an evil thing. It’s a partnership is the way I view it. 

7) As someone who develops and leads clinical trials for biologics, you also have to work with high-level agencies and regulatory bodies such as the NIH and FDA. How has that been? Any unique challenges with advancing these therapies in the U.S. versus other parts of the world?

Working with the FDA is very interesting. Over the years the FDA has been very selective about what they will fund and support, and the NIH is a big part of this. It’s about what the NIH decides they want to fund and what the FDA’s priorities are in terms of getting things into the clinic. 

In the U.S., to use biologics as an example for gene therapy, the gold standard is a phase two double-blind trial. Now in Europe, you can’t run a placebo-controlled surgical trial there. It’s not allowed. So, you can’t run a clinical trial there that has a sham surgical arm, where you put someone to sleep and you make an incision, but you don’t do the intracranial intervention. That’s considered unethical. Therefore, you have two major continents on the planet that each view how you get something through the approval process very differently. And that’s problematic in my opinion. 

I think the FDA is changing, and a lot of the biologics now are getting fast-tracked. They’re skipping steps, where they can go right to a pivotal trial for example. There’s been some signaling from the FDA that maybe you can even skip large animal studies in some instances, but that remains to be seen. So, things are changing. Some of it is probably for the good. Some of it maybe not be good, so we’ll have to see with time.

8) What advice do you have for trainees and junior staff who are looking to establish themselves as clinician scientists? How does one go about running a lab successfully but also maintain a busy clinical practice, especially in the beginning when you’re trying to prove yourself in a way?

I think we all are very impatient people inherently. I remember when I was a junior faculty thinking that I want to do X, Y, and Z, and these things are never going to happen. It feels like you’re just writing grants and they’re not getting funded. In fact, it took me 6 to 7 years to get my first R01. We’re very impatient and want things to happen right away. I remember going to meetings and just not knowing anybody; and you just feel like an outsider. These are all feelings that we go through. 

And now that I’m sort of getting towards the last chapter of my career, when I look back on it, I think there’s three phases to a career. In the first 8 or 10 years, you’re just trying to get your footing and get comfortable operating. That’s because no matter what you do, you’ve got to be good at operating. You’re getting comfortable operating, comfortable taking care of patients, comfortable taking care of complications, learning how to navigate a medical center, the politics of that. During that time, you’re just starting to get your research going. It could take 8 to 10 years to really get to a point where these things are starting to become autopilot. 

Then there’s a middle phase where you’re starting to become successful and you’re in a good spot. Some of it is luck – I hate to say that, but it’s true. Your research is finally “happening.” You’re getting into your niche and getting recognized by your peers. That’s when the fun starts. I think it’s all fun, but that’s when things get more interesting. 

Finally, there’s the third chapter, which I’m in now. This is where you’re being a lot more focused. We all want to jump to chapter two, and it just doesn’t happen that way. 

I think we must be patient and persistent—really persistent. If I had stopped writing grants after my second, third or fourth rejection, I don’t know what I’d be doing right now. You just have to be persistent. 

9) Last question – kind of tying in some historical trivia here. Any particular early pioneering neurosurgeon whom you especially admire and have been influenced by?

My answer would have to be Dr. Peter Janetta. I was interviewing for residency, and that’s when I met Peter, but I knew of him way before that. There is a biography written about Peter that’s on my shelf called Working in a Very Small Place. It’s the story of how Peter, as a resident, discovered the concept of microvascular compression of the trigeminal nerve. This was in an era where residents didn’t make discoveries. Attendings and senior attendings make discoveries. So, this book talks about his path, which was a difficult one, making this discovery as a resident, and this discovery being discounted because it was made by a resident. Very early in his career, he was really fighting to overcome this, which led to the success he had in basically building a practice and an empire around a very specific thing.

I’ve been very focused in my clinical career on movement disorders, DBS and biologics. That’s been very intentional. It was modeled after how Peter constructed his career. I don’t know if any of it was really constructed, but he just kind of fell on this path. I did my best to fall on the same path. I remember when I interviewed with him for residency, I told him this story. I doubt he remembers it, but he was really a great guy. Even though I’ve only met him a couple of times, he had a major influence on me. 

By Nehaw Sarmey, MD
University of Arizona-Tucson