Why study that, Jim Cassat?

One of the reasons I created this part of my blog was to dispel myths that I held: 1) scientists could learn a formula for approaching their projects and similarly, 2) there is a formula that scientists must follow to become a research faculty member. Neither one of these is true. Instead, scientists are good thinkers, and research faculty are hired because they have demonstrated this ability. There is no formula in science and in fact, if your science is formulaic, then you’re doing it wrong. Dr. Jim Cassat, Assistant Professor of Pediatrics demonstrates both of these points beautifully in his story.

-by Dr. Jim Cassat, M.D., Ph.D.

“You weren’t born knowing this stuff”…Only he didn’t say ‘stuff,’ and it wasn’t my first time hearing this sentence. This was a common refrain from Dr. Mark Smeltzer, my Ph.D. mentor at the University of Arkansas and a dear friend. To me, Mark was the perfect mix of scientific badass and southern gentility. What I didn’t understand at the time was that Mark had already recognized my imposter syndrome, and he was trying break it down for me in a way that even a simple Arkansas boy could understand.

Rewinding a few years may help to shed some light on this part of my scientific journey. I attended undergrad in my home state of Arkansas. I spent most of my life there until coming to Vanderbilt in 2008. I majored in biologic sciences because I thought I might want to be a veterinarian…or a physician…or a physicist. In truth, this was a lie. I really wanted to be the guitar player for Saturday Night Live. Growing up, the person holding this job was G.E. Smith, and he always looked to be having the most amazing time playing cover songs and short originals. But given the current state of my guitar playing (which was laughable at the time) I settled on the typical pre-medical route and began to take classes in zoology, botany, and microbiology. Of these, I really enjoyed microbiology, and so I sought out a research experience as many pre-med students were want to do. This search landed me in the laboratory of Dr. Mack Ivey, and we began studying an oligopeptide permease as a potential virulence factor in Clostridium difficile. This was my first introduction to molecular biology, and luckily Mack was an exceedingly patient mentor. I supplemented this ongoing experience with summer internships. The University of Arkansas has a strong tradition of (and funding for) agricultural research, and so one summer I tried my hand at making transgenic crops. We were using Agrobacterium tumifaciens to make rice and tobacco crops more disease resistant, and I also used this time to try and express the C. diff permease in crops for mass production as a potential vaccine strategy. This was a really fun project, but I would encourage anyone considering working on tobacco plants to first consider the smell of tobacco as it comes out of the autoclave. Not pleasant.

At the end of my time in undergrad, I wanted to become an infectious disease physician, but I decided against combined research training in an MD/PhD program. In retrospect, I think this reflected the major difference between doing research at an academic medical center (which I had yet to experience) vs. research at an undergraduate institution. Not that either is superior, but the careers are very different. I made the journey from Fayetteville, Arkansas (Go Hogs!) back to my hometown of Little Rock to enroll in Medical School at UAMS. It took me all of about 10 months to realize I had made a huge mistake not applying to the MD/PhD program. Our medical school encouraged early patient interactions during the first two years of the program. Although I recognized the important work that my physician mentors were doing in these interactions, I found many of my clinical experiences in adult medicine extremely depressing. I found it difficult to reconcile that even after coming up with the right treatment plan and navigating the complex social issues that many of our patients were facing, that some people simply didn’t want to take care of themselves. I also began to miss the creative freedom of the lab and working towards discovery for discovery’s sake. It was at that time that I approached the Director of Graduate Studies in Microbiology at UAMS, the aforementioned Dr. Mark Smeltzer. We spent over two hours talking about science, career options, and just life in general. I left his office knowing not only that I had options for incorporating research into my medical training, but also that Mark was absolutely the person I wanted to mentor me. And so began my love affair with Staphylococcus aureus.

The Smeltzer lab studies staphylococcal pathogenesis in the context of biofilm associated infections such as osteomyelitis and septic arthritis. I still think it is pretty amazing that the focus of my entire scientific career can really be traced back to the day I walked into Mark’s office over 15 years ago. More on that later… Mark taught me molecular microbiology, the tangled web of staph virulence regulation, animal models, how to give talks, how to write, how to meet people at conferences, and probably most importantly, how to deal with failure. I was incredibly fortunate to be admitted to UAMS MD/PhD program as a second year medical student, and I went on to complete a dissertation project in Mark’s lab before returning to the final years of clinical training. My PhD focused on how clinical isolates of S. aureus differ from the historical lab strains that had been studied for decades. This was an era just before it was commonplace to sequence bacterial genomes, and so we were relying on comparative genomic hybridizations and transcriptional microarrays. I had a mountain of data and no clue as to how to analyze it, but Mark was really great at giving you the technologic courage to push through new approaches (“you weren’t born knowing this stuff”). Mark was also great at encouraging his students to go to conferences and then making sure they got to meet everyone in the field. One such conference took place in Omaha in 2006, just before I wrapped up my PhD project. This was a conference on Gram positive pathogenesis, and one of the speakers was a new PI from Vanderbilt. This person, who appeared way to young to have an R01-funded lab and multiple Science papers, was showing some of the most beautiful images of Staph-infected tissues I had ever seen. It was also one of the best talks I had ever been to, and I remember leaning over to Mark during the talk to tell him that I wanted to work for this person. Mark introduced me to the speaker- Eric Skaar – shortly after the talk, and we shared a beer not knowing that we would be colleagues for the next 12 years and counting. I defended my dissertation, returned to medical school, and began my clinical rotations. Fortunately, this included a lot of work in pediatric medicine, which I found particularly refreshing because the patients for the most part always got better. I applied for residencies in Pediatrics with the goal of becoming a pediatric infectious diseases physician scientist, and luckily landed at Vanderbilt for my training.

It only took me two months at Vanderbilt to see my first patient with osteomyelitis. In kids, unlike most adult cases of osteomyelitis, we don’t really understand how Staph gets into bone. We assume that this is through colonization of skin or the nose followed by dissemination through the bloodstream. But of all the organs that Staph can infect in the human body, why do healthy kids frequently come to the hospital with Staph in their bones? This was a question that really bothered me, and it also really bothered the parents. They wanted to know what was different about their child that led to this invasive infection, or what they could have done differently. I also began to realize how hard it is to treat these infections. Osteomyelitis triggers a lot of bone destruction, and this bone damage makes it really hard to get antibiotics into the site of infection. Because of this, many kids with osteomyelitis will require one or more surgeries to remove the damaged bone and try to clean out the infection. And this is before they start taking months of antibiotics. I decided I wanted to study this problem as a major focus of my research career. I reached out to Eric Skaar to see if this was something he could mentor me in, with the idea being that I needed not only more training in microbial pathogenesis, but also new training in immunology and bone biology. Eric graciously accepted, and I joined his lab after completing my Pediatrics residency and the first year of a clinical fellowship in Pediatric Infectious Diseases.

My first few months in the Skaar lab were imposter syndrome at it’s finest. His graduate students and post-docs could run circles around me, not because Mark hadn’t been an awesome mentor, but because I had been out of the game for almost 4 years for my clinical training. Fortunately, Eric was also a very patient mentor, and I realized that if I just worked my butt off I could make progress even if I failed 95% of the time. Eric and I spent a lot of time making a new mouse model of osteomyelitis, with the goal of having a genetically tractable organism to study host-pathogen interactions and bone biology. After about a year a half of beating my head against the wall, we finally had some traction and began to get interesting results. We published a few papers and then I went all in for career development grants that would support my transition to a faculty position. At the end of my clinical fellowship I went on the job market, knowing it would be tough to beat all of the ridiculously awesome resources for studying host-pathogen interactions and bone biology that are available at Vanderbilt. In the end, I was extremely fortunate to be offered a position to start my own lab at VUMC. This happened in 2014, and I took two brave and amazing new trainees into the lab even before we had unpacked all of the equipment. Although I had every intention of running a bacterial pathogenesis lab, over the past 4 years the science has taken us in some very exciting new directions. Over half the lab studies bone cell biology now. We have new projects studying how inflammatory bowel disease and the microbiome impact bone. We just began work on polymicrobial infections. Sufficed to say, my imposter syndrome has also been well supported as a mentor.

I hope two major themes are evident in my training. One: it’s okay to not feel completely confident in the direction you are heading. Although many trainees worry about how difficult or stressful their ultimate job will be, I can definitively say that you also have no idea how enjoyable it can be. Trust your mentors and their guidance, but it is okay to have doubts and take a circuitous path sometimes. Second: If you love working in a particular field, find a way to stick with it. We often get told we will be penalized from staying in a particular scientific discipline or working closely with our mentors. One of the greatest joys of my job is being able to continue working with Eric and Mark. It’s important to find a way to distinguish yourself, but why should we be forced to abandon our most cherished scientific relationships?

And remember, you weren’t born knowing this ‘stuff’.

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