Maya Hoptman

Interview with Charles Dela Cruz, MD, PhD, Yale University (elected 2022)

Interviewed by Patrick Nana-Sinkam, MD (elected 2019); member, ASCI Physician-Scientist Engagement Committee

Note: The text has been edited for readability by ASCI staff.

Patrick Nina-Sinkam: Good afternoon, everyone. I’d like to welcome you to this month’s ASCI Perspective. My name is Patrick Nina-Sinkam, and today I have the pleasure of interviewing Dr. Charles Dela Cruz from Yale University. Dr. Dela Cruz is Associate Professor of Medicine (Pulmonary Critical Care and Sleep Medicine, and Microbial Pathogenesis). He serves as the Director of the Center for Pulmonary Infection Research and Treatment and the Vice Chief of Clinical and Basic Research, as well as the Director of the Physician Scientist Training Program. To give you a little bit of Dr. Dela Cruz’s background: He completed his bachelor’s at the University of Toronto and then subsequently entered an MD-PhD program at University of Toronto, and completed his MD at Yale, followed by a residency program at Yale and fellowship at Yale. He actually entered the physician-scientist research track when he arrived at Yale. His laboratory is interested in studying the role of respiratory infection in the pathogenesis of acute and chronic lung diseases. Specifically, his work focuses on how lung infection and pneumonia contribute to inflammation, injury, and tissue repair in the lung. Among his many accomplishments, he’s been the recipient of several research awards throughout his career; has served as a chair of an NIH study section, which is very prestigious; and most recently, he was elected to the ASCI in 2022.

Congratulations, Dr. Dela Cruz, to being elected to the ASCI in 2022, and thank you so much for taking the time to join us today.

Charles Dela Cruz: Thank you very much, Patrick, for the opportunity.

PN: I’d like to start out with maybe just asking you to share a little bit about your background and, importantly, your path to becoming a physician-scientist. Why not a scientist or a clinician alone? Why did you decide to pursue both?

CD: Thank you for that question. So being a physician-scientist is very new to me and my family. I grew up in Canada. Both my parents are not physicians or scientists. In fact, I’ll be the first- generation person who has graduated from a professional school or a PhD degree. I grew up in a family where they’re in businesses or commerce or computer sciences. And so when I was growing up, especially in high school, I tended towards more in the field of sciences. I felt quite interested and fascinated about it. At the same time, I had some opportunities to volunteer in a local, nearby hospital, but was really impressed by the impact of that relationship with patients. I explored that as an undergraduate in the University of Toronto, where I focused on immunology, virology — in that field. And my first experience with research was actually an opportunity from a summer research internship in a laboratory where they were studying ribozymes against HIV infection. And I thought it was kind of fascinating: something really novel, new techniques — you test out your hypotheses, trying to figure out whether it works or not, and for a disease that people are still struggling now.

And I further explored opportunities and balancing research and learning about sciences, both in classrooms and also the practical side of things. But I had no idea what a physician-scientist was all about. I actually didn’t even know they existed. And as I went along my undergraduate experience, I was exploring opportunities to help patients through medicine, but also was intrigued about the whole idea about scientific discovery and trying to figure out how that could work. To be honest, somebody told me about the MD-PhD program in Canada. There’s sort of only a few schools that provided that, and I think University of Toronto was one of the main ones. But I think it was a perfect opportunity for me at the time of my career to take a look back and really spend the time through that more formalized program to study medicine, explore science, and really integrate both. And at least for me, it was the right timing — not because I wasn’t terribly decisive about what to go for initially, but it allowed me time to explore what I really wanted to do.

So I went through the medical school classes and then ultimately contributed to a PhD thesis work on vaccine design in the infectious disease realm. And shortly after I defended my PhD, I was provided some opportunity for some additional research at Yale, which is where I kind of transferred to Yale School of Medicine and matriculated with the MD class here in 2003. Here at Yale I was provided a lot of opportunities; I explored more research and really solidified the fact that I really wanted to be a physician-scientist, because I couldn’t give up one or the other — probably because I think the experience with patients really allowed me to understand what the needs are, especially in the area that I’m interested in. I rotated in an ICU as a medical student and later as an intern and really was fully interested in that field clinically: it would fit me perfectly clinically. I loved the interaction with the staff in the multidisciplinary rounds, the consultants, patients, patient families, taking care of really critically ill patients. And it was a decision I made that ultimately resulted in a fellowship in pulmonary critical care. I still tell my mentees and applicants that it’s really important to find your clinical niche and what you enjoy doing. And then that could easily be combined with your academic passion and research interests. And for that, I still was interested in infection. So specifically, it was pulmonary infection and how that causes pneumonia, how that causes lung injury, ARDS, how it causes chronic lung disease, for example. And so that has been the main focus of my research program and research career throughout my stay here, with a lot of support and wonderful collaborations.

Your question about why not just a scientist or a clinician: I think for some people, it was very hard to do one or the other, and I think that was for me — mostly because I get engaged both from a personal level, taking care of patients, understanding their needs, but also working in the health system, figuring out what is needed. And for me, for a while, I was studying pneumonia. And it was a disease that I know a lot of people take for granted. And thinking that it’ll cause you some cold symptoms, you’ll be fine after a few days if you take some rest, some antibiotics. But really it has affected a lot of people, not only in the US, but globally. And something very simple that could be addressed, could really save a lot of lives. I think as a practicing physician, I saw there’s a need not only for more advocacy, more attention to this disease, but also pushing the field to be more sophisticated, to really personalize how we approach pneumonia and to target a treatment for our patients. And I think becoming a physician and being a physician allowed me to see that as an opportunity and a need. And so throughout, I’m trying to balance what I’ve seen in the clinic, in the ICUs, to what we study. And for example, I couldn’t have envisioned a pandemic as large as COVID to highlight this importance and that infection can really cause a multitude of problems. And in a way, I think we’ve learned a lot. I think the academic medicine scientists and clinicians are ready for these kinds of challenges. But it’s unfortunate we had to wait for a pandemic to realize a respiratory infection can really cause major damage. I think these lessons have been learned from the past, and we really haven’t learned much from previous pandemics. And hopefully, I think, from this current experience, that we can learn a lot of lessons from it. So I can’t imagine, at least for myself and for many others, to separate those two experiences. And as a scientist and a clinician, I think it could be through a formalized MD-PhD program or physician-scientist training program — which we’re currently interviewing for candidates — or MDs who have a lot of research background who are physician-scientists. And many of my mentors who are physician-scientists are MD-only. And they’ve been wonderful mentors for me. And so I think it’s been humbling experience; it’s been a rewarding experience; and I think it allowed me to really explore a lot of things, both scientifically and what we can do for patients.

PN: Great. Well, I think that’s a perfect segue into my next question. And that really delves into some of the research that you’ve done. I had the opportunity to read through some of your work — not all, there’s a lot out there, but not all of it. Your group, certainly since the beginning of the pandemic, your group has been actively engaged, really focusing and trying to understand some of those underpinnings of the dysregulation of the immune response in COVID; and furthermore, how coronavirus seems to reprogram or alter the immune system in such a way that maybe it increases our susceptibility to secondary infection, particularly bacterial infections. Given the work that you’ve done over the last few years and even the work before that, how has what you’ve learned really informed your perspective on what the strategies should be moving forward to battling COVID — which as we know is not necessarily going away any time soon — and importantly, how it might inform the development of novel therapeutics down the road for coronavirus?

CD: Thank you. Great question. Our group in collaboration with others as well here at Yale, we’ve been studying respiratory infection using basic models as well as translational studies for many years now. I think through our center, we’ve had collaborations already in place, collaborators outside our section, other departments with diverse expertise. And we were also doing biorepository samples: a patient coming in our ICU with various respiratory infections. So we were, I think, poised for COVID-19. But we weren’t expecting the proportion, the extent of the pandemic, to be honest. But it really required a big-scale collaboration with all my collaborators and other faculties — from public health, immunobiology, department of medicine, from pathology, pediatrics even — to really work together and identify that this is a big need to really set up a biorepository to understand what is going on while we were all trying to figure out what this new virus is and what’s causing. This was actually kind of nerve-racking, because we had little understanding of how much this is transmittable; can we get infected doing this? what are the protections that’s needed and handling of specimens? And so I really commend all my collaborators and the team, and not only here at Yale, but other places around the country who really try to understand COVID for the purpose of pushing our understanding and also developing more treatment. We’ve learned a lot: we learned about the new tools to identify infections. Through some of the repository work, we were able to collaborate with individuals who wanted to study how we can use saliva as a detecting tool. And so now they have a way to protocolize this approach to detect infection in the saliva. We didn’t know a lot about saliva and respiratory infections in the beginning. In terms of the use of blood biomarkers and how cellular components are different in severe disease, try to phenotype that this immune response was really dysregulated at different phases of the disease, while you are trying to tap into, for example, these patients as they progress in the stages in their hospitalization. And this is what’s happening at the same time where the clinical team and treatment team were trying to figure out what’s the best treatment regimen. What are the antivirals? We’ve all had our experience and shares of different types of drugs that have been tried and that did not work. And ultimately came up with the idea that you definitely need an antiviral treatment in the beginning, but if it’s too late in their disease course, maybe the immune response is dysregulated, and you might need some immunomodulators.

I was surprised that steroids work for COVID-19. Our experiences from a previous pandemic, the 2009 influenza pandemic, show that steroids do not work. In fact the guideline says steroids probably can cause more mortality than you think. And so the fact that globally, there are a lot of efforts to test the use of dexamethasone for certain types of patients in the hospital to calm down the immune response was really interesting, and it was probably quite helpful and really changed the course of the disease for the sick patients. And then, obviously, the significant, rapid advancement of novel vaccine strategies — and many are vaccinated — have really helped curb this infection in the various different waves. I think our own study from a basic science standpoint really found it intriguing that this SARS-CoV-2 coronavirus, when it infects cells, the macrophages, that really causes this lysosomal dysfunction — problems with deacidifications — and then really predisposes the cell for its ability to control bacterial infections. And we all know for maybe a third of the patients, after some viral infections — including influenza and now SARS-CoV-2 — that those patients are at higher risk for secondary bacterial infection because of what the virus did. And so this recent work sort of highlights that the viruses are pretty smart in terms of how they can manipulate the host. I think you mentioned earlier that these challenges for future viral epidemics and pandemics will come, and so hopefully, we’ll learn some lessons from this. But what was impressive was how the academic, scientific, and medical fields all came together to really collaborate to find out what’s going on with COVID-19 — improving our understanding of the disease and trying to identify new treatments, novel treatments, including approaches to how to take care of our patients in the ICU on the ventilators, proning. We were doing also awake proning, even, for patients based on necessity, and we learned a lot from it, and now we know that it could work. But there are also things that — we knew that this was happening already even before COVID: that the tools we’ve learned so far, so much in the ICU to take care of these sick patients, still work. Proning was known to work before; ventilators, we know, help with low tidal volume. We know that that works. We also know that influenza virus can cause all these organ diseases outside of our lung. We just didn’t pay attention to it. COVID, because it’s one big infection globally, we saw all the different types of flavors of what it can do. And so it just really accentuated and really highlighted how a virus can cause all these different organ problems.

I think what it did was, hopefully, it made these collaborations much easier. I think initially it was by necessity, and people weren’t doing anything else other than COVID. But I think what it did was it sort of highlighted the importance of data sharing, large data uses, big team sciences. I think that’s the wave of the future in terms of where science is going to go. And I think our training of the next generation of physician-scientists will have to take that in mind, that they should be able to work with other people. They can’t be just working on their own labs any more. Those are the bygone days, I think.

PN: Yeah and it’s interesting: You talk about the future, and you mentioned there at the end about the future scientists and the importance of being part of a team. And that’s really going to be the most effective way, I think, to make any major discoveries. It’s no secret that over the last several years, we witnessed a reduction in the number of physician-scientists in our field. And I know that from your CV and just hearing you talk that, really, training that next generation is something that’s a priority for you. What are some of the lessons that you’ve learned in your own journey to becoming a physician-scientist, and more importantly, what kind of advice would you give to a young resident or a fellow who might be considering the pathway of being a physician-scientist?

CD: Yeah, I think that’s an important question, because that’s the foundation for what future medicine is going to look like. And so who will be the scientists, physician-scientists who are going to be doing the research, the training, and to move the field forward in any of our fields? And what I’ve learned throughout — and a lot of it is through learning as I go, because not so long ago, there’s less of a structure; there’s less of people understanding the right pathways to physician-scientist; opportunities for funding or collaboration — there’s less of those. I think now we have more of those, more people like yourself and others in the ASCI who have gone through this and are champions of this field. There’s no one path towards being a physician-scientists, as I mentioned earlier. I think MD-PhD, if it’s the right timing for you, that’s perfect. Some people say it’s too long — that’s fine. And some people: MD and a lot of research background — it’s perfectly fine, too — to be a physician-scientist. And some decide to do a formal degree later on; it could be a PhD or it could be a master’s in bioinformatics. I think there are many paths towards physician-scientist, and so there’s no one right fit for everybody. And everyone has their own special life experiences and circumstances that make one or the other more attractive. And so that’s what I’ve learned really is — what I’ve learned and what I’ve counseled people, essentially, is that there are opportunities if you want to be a physician-scientist. And for me, I was fortunate enough to have the right mentors, who looked out for me within Yale and outside Yale to let me know, “Oh, Charles, I think this would be great for you. You should look into this.” Or people who I collaborate with say, “Why don’t you have someone in your group work with us?” Looking out for the right mentors, I think, is important for future leaders.

The other lesson that I’ve learned is there’s no real rush to really hone in what field you want to get into. I think you really, really need to figure out: this is the right fit for you clinically. And then the hardest thing, to be honest, is figuring out what your academic passion is, and there’s no rush for that either. And so for me, it’s just so lucky that what I was interested in before, I’m still interested in now. And things can change, and so I adapt based on what’s going on, but I’m still interested in that field. And I think that’s quite important to make it sustainable to the life of a physician-scientist: pushing the discoveries, pushing your clinical work, and pushing your research program.

So I encourage a lot of the trainees to learn from their experiences, try things out, try rotations, clinical rotations, even lab rotations, and what makes you tick, clinically and academically, in terms of research. I think that’s the one that will sustain many people, including myself. Because when I attend the ICU, I love it. I’m there one week at a time, as you know. It’s really energizing. You know exactly: this is the field you want to get into. Sometimes the nurses would say, “Well, when do you come back?” I always tell them, “Well, I do this research thing on the side [chuckle], and won’t be able to come back any time soon, but hopefully.” We have to partition our time well. And that’s really, really an enjoyable and rewarding career, and I’ve been fortunate. I know my parents, who are not in the field, always ask me, “When do you stop training?” I think there was one point I stopped telling them I graduated from something [chuckle] — or be it a fellowship or something else. It’s a lifelong process. And so I think the way they’ve seen me going to the lab or working with a laptop here and there and sometimes, I think that’s part of the physician-scientist — I think with the realization that you have to have a well-balanced work life. And I think that’s why it’s harder for people, and the purpose for why you’re doing this — it’s really important, And to have the right support system is even more important, I think.

PN: Well, I know I speak for everyone in saying that we’re fortunate to have you as a member of ASCI. And certainly, the fact that we’re in the middle of this pandemic, we’ll be looking to your lab and others in guiding us in terms of that next phase of how we’re going to manage COVID and other infections. I really, on behalf of all of the ASCI, I really want to thank you for taking the time. I know you’re very busy, and I appreciate you taking the time to be with us and, of course, wish you the very best in the future.

CD: Thank you very much for the opportunity.

Interview with Valerie A. Arboleda, MD, PhD, UCLA (elected 2022)

Interviewed by Patrick Nana-Sinkam, MD (elected 2019); member, ASCI Physician-Scientist Engagement Committee

Note: The text has been edited for readability by ASCI staff.

Note: The text has been edited for readability by ASCI staff.

Dr. Patrick Nana-Sinkam: Good afternoon, and welcome to ASCI Perspectives. My name is Patrick Nana-Sinkam, and today I have the pleasure of introducing Dr. Valerie Arboleda. Dr. Arboleda is Assistant Professor of Pathology, Laboratory Medicine, and Human Genetics at the University of California, Los Angeles. Dr. Arboleda has been very successful in a relatively short career, having been awarded the NIH Director’s Early Independence Award and several other NIH awards as well as fellowships. The Arboleta laboratory is focused on applying genomic tools and large data sets to understanding how both rare and common human genetic variations lead to human disease. Dr. Arboleda, welcome and congratulations on your recent election to the ASCI.

Dr. Valerie A. Arboleda: Thank you very much. I’m honored to be a part of the ASCI community.

PNS: Dr. Arboleda, I’d like to ask you as a starting question to share with us a bit about your career path, and in particular your background and what attracted you to this path as a physician-scientist.

VAA: I’ve been thinking about that a little bit more recently as I’m mentoring students. It’s not something that I think there was an active decision. It kind of fell into place, and I think a lot of things aligned to help me make that decision, to help that decision be easy. I personally come from a long line of health professionals. I have a lot of relatives . . . So, I’m Filipino, and my parents, they’re both physicians, they work in primary care. They immigrated here from the Philippines just before I was born, and that immigrant community sort of lifestyle — they were physicians; I have a lot of family nurses, physical therapists, working as CNAs [certified nursing assistants] all over the health professional community. And the focus when I was growing up was really around: find a good, stable job. I did not know a lot of scientists. I would say that I went to college, that was the first time I really sort of said, “Well, what do I need to do to go to med school?” And people had told me, “You should go and join a research lab,” and so that’s what I went and did. And that was my first introduction to science.

And I stayed in the lab for four years, and it was not to check a box on the CV, but it was because I really, really enjoyed it. And at the end of that four years of training, I thought to myself, “Well, I could do an MD-PhD. I don’t really know what that path looks like, that’s a really long road.” And so I applied as an MD . . . I don’t want to say MD-only, because that makes it sound like it’s “just” an MD, but I applied as an MD, and I ended up at UCLA. I had in the back of my head thought, “Well, if I have a chance to do a little bit more research, let’s explore that a little bit more.” And so when I saw this HHMI [Howard Hughes Medical Institute] Medical Fellows Scholars — it’s a program where you can take a year out between your second year and third year of med school, or between your third and fourth year — I did that and I kind of just fell in love with research. I didn’t want to go back to med school, and so when I spoke with the program directors of our MSTP [Medical Scientist Training Program], they had me do a formal application. I did the interview process, and they said, “Well, we’ll take you.” That sort of started me down a path, and I never really looked back at that point.

I did finish my PhD, I finished my MD, and then when that decision point came to do a residency, I think it was just — it was another decision tree for me: Do I want to see patients? Do I want to do more research? And that was a much harder decision, because when I went into med school — when many of us go into med school — you go in because you want to help people and you want to see patients, and that was a very hard thing for me to give up. But in the end, I realized if I had to make a choice and just do one, I really wanted to have a research career. And so I ended up doing pathology and lab medicine because I couldn’t quite let go of the clinical aspect. And that was a really fun residency, because it is a lot more . . . I won’t say research-oriented, but you do learn a lot more about the ins and outs and how the black box of a diagnostic testing works. It’s almost like being in a research lab in some ways. Once I was in laboratory medicine, I think, I was doing research, I was helping out building new tests, and that kind of got me. And I fell in love with both genetics and testing, and those two things just . . . those jibed. I had done my PhD in human genetics and looking at rare diseases, I could do genetic testing, and it all fell into place, and that’s why I’m still here, because it was an amazing research experience.

I had really supportive mentors all throughout my training: people who I knew really well and people who I met along the way, including some faculty who I now know are part of ASCI, who told me, “It’s a long road, so take your time and do it the way you want to do it. And don’t let people push you down and tell you that it’s not worth it, because it’s a really fun career.” And at the end, when you’re able to run a research program and mentor students, I’m kind of on that other end looking back and thinking, “Wow, this is really fun, and I really enjoy all parts of my job” — less so the bureaucratic pieces — but all of the parts where I’m working with students and we’re doing new discoveries and being the first people to see certain types of data. It’s been really fun.

PNS: I want to ask you a little bit about that, that path that you’ve taken. You’re at this really, I think, unique intersection between genetic testing and clinical medicine, and I know that your laboratory has really been focused on: How do you go about integrating these large data sets, and how do you make sense of them? Which is really something that those of us who are novices struggle with. We don’t have a lot of understanding, so you’re really an emerging expert in this area. I want to ask you about this in the context of the COVID pandemic. I think there’s so many things that we’ve learned about the COVID pandemic: it’s highlighted the inequities that exist in health care, broadly speaking. It’s also highlighted the importance of rapid drug development and the fact that we can, if we mobilize all of our forces, develop drugs relatively quickly if we’re all focused in. And it’s also highlighted some of the shortcomings that exist in point-of-care testing, and how do we get widespread testing to broad communities, particularly communities that sometimes don’t necessarily have access to that testing? How do we do it in an efficient way, in a specific and a sensitive way, when we think about diagnostic testing?

So with all of that in context, can you share with us some of the work that you’ve done, really in collaboration with many colleagues, in trying to address this issue of the testing in COVID? I know that you worked on something known as SwabSeq, and you’ve published some papers in that space. Could you share with the audience how that came about and where you see that work going?

VAA: Yes. SwabSeq was sort of a really fun . . . I’ll call it a detour. As a resident when I was in training, one of my favorite rotations was actually with our infectious disease group. I worked closely with Omai Garner, who’s now our Director of Clinical Microbiology. And when I started my research lab, I kind of moved away from infectious disease because I’m not trained in infectious disease or in microbiology. But I am trained in genetics, so when the pandemic started, there was a number of my colleagues from both human genetics and computational medicine who said, “This is sort of strange, we’re a genetics department, this is qRT-PCR, we do this in our sleep. This can’t be that hard. We should help with testing, because we can’t leave our house because we can’t get tested, there are no resources.” And so we worked closely, we said, “Well, there’s got to be a way to do this that’s a little bit more scalable,” rather than the current methodologies, because they’re relatively small-scale, there’s a lot of pipetting involved, there’s a lot of manual labor — which is I think part of the reason why it takes so long. Imagine trying to take a thousand water bottles, pipette out a little bit from each water bottle into a new tube. That process is fine for maybe twenty samples, but once you’re scaling up to hundreds and tens of thousands of samples, it’s sort of untenable and requires either some automation or some tricks along the genomic testing pipeline.

And so we developed SwabSeq, and it’s called SwabSeq although we don’t test very many swabs. We actually do a lot more with neat saliva, saliva that people just spit into a tube and that was a way . . . There was a lot of problem-solving throughout that whole process, and I would say the genomic technology was relatively easily. The technology is pretty similar to a regular RT-PCR, the traditional fluorescence-based RT-PCR that most clinical labs run. There are three major differences, I’ll say. One is a readout sequencing. So it’s a digital readout rather than a fluorescence read-out, so that in theory enables a little bit more sensitivity. Because it’s a sequencing-based readout, we have primers that are unique per well of your PCR plate. And so those unique primers that are tagged onto the barcodes — the DNA barcodes tagged onto the primer set — those allow us to pull all the samples together once we’ve amplified the virus and then sequence it. And then we can deconvolute everything and we can figure out, exactly, based on the bar codes, which sample was positive or negative. And then the third thing: So as a genomic technologist, if you had told me this, I would have said, “Well, you have to normalize all of your values and then you’re going to spend all this time normalizing the DNA or RNA across your samples before you amplify.” And we get around that using endpoint PCR, and we include what I call a standard. So it’s essentially a little piece of the virus that we try to amplify that our primers amplify. But we’ve synthesized it, so it has six base pairs that are reverse complemented in the middle, and that allows, due to our sequencing readout — we can actually detect whether our primers worked and how well the amplification within that well is. So we have an in-well normalization that allows us to really be a lot more accurate with our quantitation. Our quantitation is a ratio compared to the Ct of a regular qRT-PCR.

But that technology, we’ve had that for a long time in genomics testing. It had never really moved into clinical lab testing because it’s sequencing, it’s complicated, the FDA doesn’t have a good way of regulating that. And just bringing up genomic testing in a clinical setting just has a lot of extra regulatory challenges that haven’t been fully worked out yet. There’s I think a lot of challenges in trying to, one, get that testing out there into the world. But I think the bigger challenge, it’s not necessarily the testing, but the bigger challenge is really logistics. Because of the way our health care system is designed, it’s really just not that easy for people to come and deliver samples to us. That operational logistics of testing, getting them to a specific site for the scalable testing, I think, proved to be one of the harder challenges.

And then the other challenge we had was we needed this process to be so simple, we had to go ahead and design our own swabs that had break points at specific sections. If we wanted to scale it, we needed to have the same tubes used for both saliva and nasal swab. And that worked really well and still continues to work really well, but has a lot of interesting other challenges when you’re trying to 3D print swabs or to manufacture tubes from different sites. Even companies that sell us their tubes that are automatable, different lots have different efficacy as far as how easy they are to open. And so with automation, you have a different set of challenges that we’ve come across in this particular process. But the technology, I think I’ve always said, is fairly straightforward. It’s really just the logistics and how do people pay for a test, how do people get testing. In Los Angeles, we’re a huge — ten million people — but it’s a huge county: How do we get tests into one location? We didn’t have that infrastructure in place, and I think it’s a little bit better now, but still leaves a little bit to be desired given the rates of COVID right now in Los Angeles.

PNS: As we talk about genetic testing and use of big data sets to really, I think, ultimately inform clinical decision-making — because that’s why we’re all here, we want to obviously improve human health, that’s the whole point of doing all of this — would you be kind enough to reflect and maybe more forecast on where you see this integration of large data sets going in terms of informing clinical decision making? Where do you see artificial intelligence maybe fitting into all of this as we become more and more sophisticated in diagnosing rare diseases, or even common diseases, and making clinical decisions?

VAA: That’s a really great question because we are just . . . In genetic-based testing, I think we’re just in our infancy. We have a lot of data. Millions of people around the world have had their genomes fully sequenced. But I would say that a lot of the data that we have right now is very European-centric. And so that data is there, and for certain groups in our population, we can make pretty good predictions for things where we have a lot of data, things that are quantitative, like LDL levels or risk of heart attacks that we have a lot of data in the electronic health record [EHR]. But I think a lot of that, it’s not as strong in populations that aren’t as well sequenced, where we haven’t done those studies in enough individuals to see even the smallest effects of a specific variant in our genome. And so I think there’s still . . . I think a lot of people have noted this, and there’s a lot of work being done trying to improve equity amongst genetic testing, particularly in who we’ve sequenced and trying to make sure that we’ve included all groups and we’ve really taken into account all the different variabilities around what I’ll say is like genome-wide association testing — so those small effects.

I think the groups that have come the farthest have been in cardiac testing, risk of heart attacks, and increased lipids, so hyperlipidemia. But there’s still a lot more work to be done. So in the rare disease spaces, most of the individuals who are able to access genetic testing come from individuals of higher socioeconomic background, and so we don’t have a lot of data on how these specific variants might act in other populations and underrepresented populations. And then I think even sort of more broadly, when you think about genetic testing in the EHR, what I learned about genetics in medical school is very different even — and that wasn’t super long ago, it was long enough ago — but it’s different than what we’re able to put out now, the types of reports people are getting and the types of direct-to-consumer genetic testing that are out there. And so I think there’s still a huge need to educate the physician and the health care provider workforce on these types of tests and when to refer.

I think artificial intelligence can help us in some ways, but there’s still . . . We need to make sure that the tools we have and the data sets that we’re feeding into these neural networks and these artificial intelligence are also equitable and diverse, so we’re just not replicating the inequities that currently exist. We’re just not replicating them and not realize that we’re doing that when we put them through these artificial intelligence. And don’t get me wrong — I think there’s a place and it’s going to really revolutionize the way we do health care, but we just need to also take a step back and make sure that when we implement any of these systems, that they actually do what we think they do rather than replicating existing structures.

PNS: Well, as we move forward in the field of genetic testing, we’re certainly going to be looking towards you and your team and others in leading the path for us. I sincerely want to thank you for taking the time to share your journey as well as your perspectives on genetic testing. I know it means a great deal to the ASCI to have someone of your caliber joining the membership. And of course, we wish you the very, very best for the future. Thank you so much for taking the time.

VAA: Of course, of course. Thank you so much for having me.

Interview with Consuelo H. Wilkins, MD, MSCI, Vanderbilt University (elected 2022)

Interviewed by Patrick Nana-Sinkam, MD, Virginia Commonwealth University (elected 2019); member, Physician-Scientist Engagement Committee

Note: The text has been edited for readability by ASCI staff.

Dr. Patrick Nana-Sinkam: Good afternoon, everyone. My name is Pat Nana-Sinkam. I’d like to welcome everyone to our inaugural “ASCI Perspectives.” It’s my pleasure to have as our inaugural interviewee Dr. Consuelo Wilkins. Dr. Wilkins is Chief Equity Officer and Senior Associate Dean for Health Equity and Inclusive Excellence, Associate Director of the Vanderbilt Institute for Clinical and Translational Science, professor of medicine, Division of Geriatric Medicine, and elected member of the ASCI in 2022. First, Dr. Wilkins, thank you so much for being our inaugural interviewee, and secondly, congratulations on your recent election to the ASCI as well as being elected to the National Academy of Medicine in 2020. Welcome, Dr. Wilkins.

Dr. Consuelo H. Wilkins: Thank you so much. It’s my pleasure to be with you.

PNS: So, I’d like to start off by maybe just hearing a little bit about your journey to becoming a clinician-scientist. Would you be able to share with us your path to being a clinician-scientist, and what in particular attracted you to that pathway for your career?

CHW: Yes, absolutely. Let me start with saying, honestly, I had no intention of being a scientist. I started my career, my medical education, thinking that I would be a clinician — perhaps I would spend some time doing education. I grew up in a small town where people around me, people that I love, didn’t have a lot of access to health care, and that was at the forefront of my mind. That’s what I really wanted to do, is take care of people, especially older adults. That was a passion for me early on. After I finished medical school at Howard and was doing my residency in internal medicine at Duke, I had this series of experiences where I saw Black women coming into the hospital with hip fractures. And I noticed that they weren’t getting the same treatment after they had their hip surgery. They weren’t going home on calcium and vitamin D. Bisphosphonates were just coming out — they weren’t going home on those. And I started to ask, “Why aren’t these Black women going home with the same treatment and follow-up for DEXA scan?” And the answers I got were, “Black women don’t get osteoporosis,” and so that’s what I learned as well.

Black women didn’t get osteoporosis: but why were they coming in with hip fractures? These were not traumatic injuries, motor vehicle accidents. These were just falls, and they were breaking their hips. So it was the classic presentation of an osteoporotic hip fracture, and that led me to doing a lot of research . . . I shouldn’t say research — reviewing the literature, looking for answers, and realizing that the answers weren’t really there. And that was really when I shifted and said, “You know, there are so many things that we do in medicine that don’t have enough evidence for specific populations,” and that’s really what started my pathway into doing clinical research. As I mentioned, it really wasn’t something that I was focused on doing, and once I got started with the questions and developing hypotheses and aims and all of the strategies that we put into really good research, I was hooked after that. But I still thought — it was still something like, “No, this is taking a lot of time” — but no, everything that kept bringing me back was, we need more answers. And so that’s really what started my journey.

PNS: Great, thank you so much. It’s a perfect segue into some of the areas that you’ve really focused on, one of which is community and stakeholder research. It’s obviously both very timely, it’s important. And we know that it’s important that all communities have the opportunity to benefit from implementation science, transformational basic science, and clinical research, yet many centers struggle with community and stakeholder research. Given your wealth of experience and what you have seen, what you’ve learned throughout your career, what are some of the keys to really successfully engaging communities as active partners in research?

CHW: Well, Pat, you’re going to start to hear a theme now. It’s going to sound like I didn’t want to do anything that I am actually currently doing in my career. So my path to actually starting to do community engagement was also one that I wasn’t intending to do. As I was starting my research career and focusing on minoritized populations, especially African Americans, you know: we’ve got to get this evidence created, we need people to participate in research. And of course, as you know, so much of our research does not include the populations that are most impacted by the diseases. And so, how do we get these racialized minorities to participate in research? I’m designing my whole study focused on this, so now I have to actually come up with strategies and methods to involve them. And honestly, it was not as easy as I thought it was going to be. I’m sure other people have that experience as well. And I learned early on by working with the community that I had to engage them in meaningful ways in order to get the work done. So, if I were advising researchers and institutions in general, I think an important piece of what we do in community engagement is setting expectations that our research has to change based on this engagement.

A lot of times, we come up with these plans and goals, we have the research study, it’s perfect, and really all we need people to do is get in line and do what we want them to do. And if we take a step back and realize that if that were going to work, then it would have worked already. That’s not going to be the answer to the discoveries that we need to solve some of the most pressing health disparities. So if we’re going to do engagement, we have to approach it from the standpoint of humility, and in particular, cultural humility — that we don’t have all the answers, we don’t know the approaches, we don’t know what people need to engage; and also sometimes we’re not even designing the studies in a way that would be meaningful for them to participate in or even answer the questions that are of interest to them. I think an important part of that is when you’re level-setting, understanding your positionality when you’re designing your research. The lens that you’re bringing to the work has to have some room to be changed, shifted by the input from community members.

It turns out that I wasn’t so bad at engaging the community when I started to do it for my own research. I learned to listen intently, to think about the mutual benefit to others. And of course, when I was getting my master’s in clinical investigation at Washington University, there was not a single day that we talked about community engagement. The pathway for learning these skills really required me to work more with people in public health, in sociology, in  humanities and social sciences, and it took a lot of time. But once I started to do it, my colleagues said, “Oh, you’re good at that. Can you do it for me? Can you help . . .” Well, how am I going to do my own research if I’m doing it for everyone else? And that really led to  — thanks to really the CTSAs [Clinical and Translational Science Awards] — providing more of a structure for us to do community engagement in a sustainable way. Over the last decade or so, a lot of my work has focused on really building the infrastructure so that we can easily shift and engage communities in a meaningful way by developing these long-standing partnerships with them and thinking about what it is that they need or want in order to involve them, but also really leveraging that knowledge, that expertise, that lived experience that people have, and turning that into information that can be embedded into our research. I don’t know if I answered your question. Did you want to follow up?

PNS: No, you absolutely did answer that question, and I’m so glad that you gave it such a comprehensive answer. It’s an area that we struggle with, and I think there are so many misconceptions when it comes to community and stakeholder research. And as a result, we often take the wrong path in trying to implement it. So I very much appreciate that. One thing I’d love to ask you is really, as you reflect on your career, and I really think this applies to all of us: There are lessons learned; there are always lessons learned along the way. And it’s important — we have a responsibility to hopefully pass on some of those lessons to the next generation of scientists, the physician-scientists, the up-and-comers, as we like to say. What are some of those lessons for you that you would want to pass on to any young colleagues who might be listening to this?

CHW: Yeah, I think the humility piece that I mentioned already is one that I think is such an important lesson. The idea that — after all of the training and education that we’ve had to become physicians, to become researchers — to really acknowledge that there’s so much that you don’t know. And I often give the example based on the lived experience: If you’re studying diabetes and you don’t have diabetes, you never lived with someone who has diabetes, it does not matter what you know about clinical pharmacology, about medicine, about research methods. There’s so much you don’t know about what it takes to engage a person, involve them in the research, but also how the impact of the discoveries will affect them or even whether or not they will uptake or use any discoveries that we have. And making sure that we’re always recognizing the variety, the diversity really, of expertise that’s available to us is so important. And often, we’re not humble enough to really appreciate all of those things.

The second thing I would say is to push back against those who think that your ideas need to fit into a narrower lens or a smaller box. One of the things that I heard — or some of the things that I heard early on in my career, especially when I wanted to study disparities — is that it’s not sexy enough, or this is not going to be viewed or reviewed in a way that will get you funding. And I think we have to balance that with: “Okay, well, everybody’s telling me to be innovative, and now you’re telling me it’s not enough like everybody else is doing.” Learning how to push back, look for other ways, alternative strategies for getting your work done, I think is so important really for your independence. And being able to say, “Okay, I appreciate the ways that others have done it; I’m grateful for the paths that have been paved already. But this is something that is important, meaningful, and I think is worth studying, and I would love to have others around me to help me think about ways to do what I want to do” — not just that: “In the state that it’s in now, it’s not doable.” So I think sometimes, that requires a lot of back and forth and some political savvy in order to get to that point.

And then the last thing I would say is that something that I learned really early in my career is that if I can’t communicate my research to the public, then I’m not going to be able to do a good job in this work. We spend all of this time, of course, thinking about the language that we need and polishing our vocabulary so that we can demonstrate that our work is so rigorous, and then we can’t explain it to the average person. And for clinical researchers in particular: being able to really talk about the public health relevance and significance, especially when we’re getting NIH funding. This is public money, so we have to be able to communicate effectively about our research. And I think that has broad benefits, not just for communicating directly to the public and stakeholders, but also for funders — and a broad range of funders. So, those would be perhaps the three things that I would offer.

PNS: That’s fantastic. I learned something already, and I think I could benefit from some of those lessons myself. But I’m definitely going to take those for some of my mentees, so I thank you for that. Honestly, I could talk to you for much, much longer. I’m sure there are many things that we could discuss, particularly in community and stakeholder engagement for sure. But I really want to thank you for taking the time. I also want to congratulate you again on the National Academy of Medicine as well as ASCI election. They’re amazing accomplishments — you should be very proud. And I do again appreciate you for taking the time, and of course, I wish you the very, very best in the future. Thank you so much.

CHW: Thank you again.

Interview with Courtney D. Fitzhugh, MD, National Heart, Lung, and Blood Institute, NIH (elected 2024)
Interviewed by Vijay Sankaran, MD-PhD, (elected 2018); member, ASCI Physician-Scientist Engagement Committee

Note: The text has been edited for readability by ASCI staff.

Vijay Sankaran: Welcome to this ASCI Perspectives interview. My name is Vijay Sankaran from Boston Children’s Hospital and Harvard Medical School. It is my distinct pleasure to have as today’s guest for our Perspectives interview Dr. Courtney Fitzhugh. Dr. Fitzhugh is a Lasker Clinical Research Scholar and heads the Laboratory of Early Sickle Cell Mortality Prevention at the National Hear t, Lung, and Blood Institute. She’s a pioneer in advancing the use of hematopoietic stem cell transplantation in sickle cell disease. Dr. Fitzhugh earned her medical degree at the University of California, San Francisco. While in medical school, Dr. Fitzhugh participated in the National Institutes of Health Clinical Research Training Program and worked with John Tisdale during this time. After completing her MD, Dr. Fitzhugh did a combined internal medicine and pediatrics residency at Duke University Medical Center, and then did a combined adult and pediatric hematology fellowship at the NIH and Johns Hopkins Hospital. Dr. Fitzhugh is widely recognized for her groundbreaking studies in applying hematopoietic stem cell transplantation in sickle cell. She’s a member of the American Society of Hematology and a newly inducted member of the American Society for Clinical Investigation. Dr. Fitzhugh, welcome to this Perspectives Interview.

Courtney Fitzhugh: Thank you for having me.

VS: To begin with, I was wondering if you could tell us a bit about yourself, your training path, and what initially got you interested in science and medicine.

DF: Sure. I’m originally from California. I grew up in San Jose, California. My father was a family practitioner, and I used to go with him to the office. I was his medical student — I’m sorry: I was his medical assistant when I was in late high school. I just really loved working with him. I loved that he had those great relationships with his patients, the continuity of care. Initially I wanted to do family medicine, until I went to medical school and realized I was much more interested in taking care of sick people. And so I read about sickle cell disease and just was really excited about it, the fact that it affects children and adults, so I can still have that continuity of care. It impacts any organ system in the body, so everybody is different. And just from reading the pain and the disparities associated, I felt like it was a place where I could make a difference.

And so when I went to medical school, after my first year, I did research in the lab over the summer, and I really liked seeing the patients more than I enjoyed being in the lab. So I really was interested in the clinical aspects of it and got interested in clinical research. As you mentioned, I went to the NIH after my third year of medical school and met John Tisdale, and he gave me the opportunity to work on developing a new curative approach for sickle cell disease. So since then I’ve been hooked.

VS: Wow. That’s amazing. Now you talked about the impact that being a medical assistant for your father had upon you. I was wondering if you could talk a little bit about the impact more broadly about mentors that you’ve had in your career and how this has helped shape the paths you’ve taken as a physician scientist.

DF: Yeah. It’s been critical at every single stage of my career. Going back to John — and I just had such a wonderful time with him: seeing patients, the way that he interacted with the patients, just how caring he was, and how much of an advocate he was — or is — and how committed he is to my success. He’s been incredible, and I’ve had so many different mentors in every single aspect. So I’ve been interested in talking to women and how they balance work-life balance, and then people outside of the NIH who can give some advice. And I’ve really  — That’s one of my favorite things now about having a lab, is actually being able to pour into the next generation and mentor others.

VS: Wow, that’s really great. Along the way, and you sort of alluded to this, it sounds like you’ve described the value of having mentors not just at earlier stages of your training or when you were sort of . . . before you started your training, but actually even now as a laboratory head. And I was wondering if you could comment on the importance that you view of mentorship and how you believe mentoring others can also help in this process as well.

DF: Yeah, mentoring . . . I think one of the best stories I have about mentoring now is: Just recently, I went to a Cure Sickle Cell meeting, and I started talking to Michael DeBaun about my interest in long-term health effects of curative therapies. And just from that discussion, we started a collaboration and applied to — successfully awarded — a U01 award. And so working closely with him and helping me with writing my first grant at this stage of my career was really critical. And now being able to do that for others, helping my trainees with their presentations, with abstracts, with manuscripts, it’s just really fulfilling and exciting, being able to see others succeed.

VS: That’s terrific. That’s really amazing. And it’s really just such a testament to both your own mentors, but also giving back and continuing that process and helping support people.

DF: Thank you.

VS: So I want to switch gears a bit. You have and you continue to contribute tremendously to advance our understanding of how we can apply hematopoietic stem cell transplantation using allogeneic and autologous sources to cure sickle cell disease. This has been an exciting area, with lots of recent activity. Could you tell us about where you see this research field going in the coming years and what advances that you’ve been most excited about?

DF: Yeah. This is a real critical time not only just for curative therapies. I remember when I first went to my first American Society of Hematology meeting, you would hardly see anything about sickle cell; it was very few and far between. And now, there’s so much, I can’t even get to it all. So, just in the short period of time that I’ve been in the field, seeing how much transformation, all the new drugs that have been FDA approved or are being developed — but in the curative therapy setting, it’s really exciting. As you mentioned, we have both allogeneic and autologous approaches. Unfortunately, the most successful traditionally has been HLA-matched sibling transplant, but less than 15% of sickle cell patients have an HLA-matched sibling donor. So what are the options that are available for others? So, now we have haploidentical transplant, where you increase the chance they have a donor to 90%, because most patients will have a parent or a child or half-sibling who could serve as a donor, or even you could use cousins and nephews and nieces. So that increases the donor pool, and there’s been some exciting new discoveries and new conditioning of regimens that have been successful — and even in the haploidentical setting with results that are approaching the HLA-matched sibling setting. So that’s been really exciting for me, since that’s my interest. And now what I’m trying to do is apply these exciting results to patients who have compromised organ function, who are very frequently left out of clinical trials. In the gene therapy and gene editing areas, there’s also a lot of excitement there too. The biggest limitation is that they use high-dose chemotherapy for these gene-corrected cells to be able to have the advantage. What is exciting in that field is using antibody-based conditioning in order to clear out the patient’s own autologous cells.

So whenever they get that to work, that’s going to be a really exciting endeavor. And then in vivo gene therapy, where they won’t have to do a lot of the manipulation outside the lab, but just being able to inject the cells and ideally cure them that way. So that would give a lot of patients, hopefully even outside of the US, access to this care. So I just love . . . Because people ask me, “What’s the future for haploidentical transplant in the setting of gene therapy and gene editing?” But I just think it’s so great that the patients have these options to choose from. There’s pros and cons for both, and right now we don’t even know the short-term or even the long-term success and toxicity associated with these approaches. A lot more work is done, and I’m excited to be able to work some to contribute to that field as well as others.

VS: Wow, that’s tremendously exciting. I want to also go back to something you mentioned earlier when you were talking about mentors, and you were talking about your work with Mike DeBaun and this recent U01. And it sounds like this was focused around long-term complications of some of these therapies. And I was wondering if you could comment a little bit, because I know you’ve thought a lot about this issue, about what we also need to do and where more research is needed in that space.

DF: Yeah. Thank you for asking. So we’re really interested in how . . . We’re not just trying to cure the patients in the short term. We’re trying to reverse their disease and help them to have a wonderful quality and quantity of life that’s long-term. Unfortunately, a lot of times, the patients are transplanted, and then they’re referred back to their doctors and sometimes they’re not followed for the long term. We really don’t know what’s happening to these patients. So we’ve tried to get some of the biggest transplant institutions together, which includes Children’s National Hospital in DC, Vanderbilt of course, NIH, Emory, and Hopkins. And to look to see, looking not only at the survival, graft-versus-host disease, which a lot of people look at, but what’s happening to the heart, the lung, the kidneys. These organs when damaged lead to early mortality in adults with sickle cell disease.

But we’re also excited that we’re going to be able to compare how nonmyeloablative or the lower-intensity conditioning compares with myeloablative conditioning, transplanting adults versus transplanting children, doing transplant versus standard therapy, not transplanting them — and be able to follow these patients. We’re going to have about 20 years of data between the retrospective and the prospective collection of the data and reporting of the data. So we’re really excited to see — and this is the only way we’re . . . And we’re also including people who have undergone gene therapy and gene editing. So I’m really excited to see what we’re going to find.

VS: Wow, that sounds incredibly important. And also just so needed, because while there’s so much excitement around these emerging approaches, obviously there’s a lot of work to be done to understand, what are the long-term consequences of all of these changes. So that’s tremendously important. So I want to move on to a slightly different area. Many of our viewers of the series are likely physician-scientist trainees, including those from traditionally underrepresented backgrounds in medicine and science. I was wondering if you could comment on lessons you’ve learned in your own training as a physician-scientist and what advice you might give to trainees who are watching this interview.

DF: So I would say, one of the most important things is just to realize what you’re passionate about, what excites you. Because I love going to work every day because I’m so excited about what I do. So it’s not really about making the money or where you’re going to make the most money, but where are you going to be happy? Where are you going to be able to make a difference? And I’d also say just to . . . I used to struggle with imposter syndrome. I came to the NIH because I wanted to work with John Tisdale. I wanted to support his research, and that door was not open to me. He only had one position, and it was already filled. But this other door swung wide open, and if I had had fear and didn’t walk through, I wouldn’t be where I am. I would say look for those doors. Where are those doors opening? So that all you have to do is just walk through. And then look to see what success you’ll have and how you’ll be able to make a difference in the lives of your patients and others.

VS: Wow, that’s such great advice. And I think even today it’s such an important thing that I as I think about different opportunities always, it’s hard to get perspective on that. So this has been such an enlightening and fantastic discussion, Dr. Fitzhugh. I was wondering if you could provide us with some closing thoughts for this audience and any other thoughts that you might have about the work that you’re doing or areas that physician-scientists can think about as they develop.

DF: Yeah. I just love being able to be an advocate for my patients with sickle cell. A lot of them go to the emergency room, and no matter where they are in the US or even outside the US, they’re treated like . . . people don’t believe that they’re having the pain. And it’s just so frustrating and disappointing hearing the same story from the patients over and over. But being able to develop relationships with these patients, develop trust with these patients, and then offer them an opportunity to have a new life that doesn’t involve pain and fatigue. And it’s just  so wonderful. So just look for the way that you’re going to be able to make a difference in the lives of your patients.

VS: Well, thank you so much, Dr. Fitzhugh. It has been truly outstanding to be able to chat with you today.

DF: Thank you for inviting me. I appreciate it.

Interview with Juan Pablo Arroyo, MD, PhD, Vanderbilt University Medical Center (recipient, 2022 ASCI Emerging Generation Award)
Interviewed by Jennifer S. Yu, MD, PhD (elected 20218); member, ASCI Physician-Scientist Engagement Committee

Note: The text has been edited for readability by ASCI staff.

Jennifer S. Yu: Good afternoon and welcome to the ASCI Perspectives. I am Dr. Jennifer Yu from the Cleveland Clinic, and today my guest is Dr. Juan Pablo Arroyo. Dr. Arroyo is an Assistant Professor of Medicine at Vanderbilt University. His research has focused on understanding fluid dynamics and their regulation of metabolic diseases. Dr. Arroyo is a recipient of the ASCI Emerging-Generation Award in 2022. He is also the recipient of the 2020 Robert Wood Johnson Foundation Amos Faculty Development Scholar award. Dr. Arroyo, thank you for taking the time to speak with us today and sharing your words of wisdom.

Juan Pablo Arroyo: Thanks so much for the invitation. I’m really happy to be here.

JSY: You had an interesting path to becoming a physician-scientist. You obtained your MD at the Universidad La Salle in Mexico and followed that up with a PhD. Was there something in particular that attracted you to this career path?

JPA: I’ve been a little bit of bouncing around. I started medical school in Mexico. You just do six and a half years straight out of high school. And I met my physiology professor — he’s a basic scientist, and he basically taught me to love physiology. And once I finished my MD, I was dead set on becoming a surgeon in the US because of some rotations that I had. And I had a required year of research that I was doing, and I was in his lab and I just loved it. So I ended up getting a PhD in kidney physiology. And it was basically for the love of understanding why things happen the way they do, more so the diseases; it was understanding how the body works. Never second-guessed the surgeon part. And I ended up doing so: I did the MD, then I did the PhD. And then I got a prelim position as a general surgery resident at Yale. I did a year there, and after that I realized surgery was definitely not for me. So I ended up doing a two-year postdoc in renal genetics and hypertension in Rick Lifton’s lab. And that was an amazing experience that taught me an enormous amount.

And after that I came to Vanderbilt, where I’m at, and I did the physician-scientist training program. So I did two years of internal medicine, the year of clinical nephrology, and then I was asked to be a chief resident. I was a chief resident for a year, then went back into the lab, started research, and then got promoted to faculty. So it’s been a little bit of a circuitous path to get to where I am now.

JSY: Wonderful. And it really speaks to how teachers can be so inspiring to students and how they can really change your trajectory.

JPA: Oh, 100%.

JSY: And I’m so glad you followed your heart and decided what was most important to you and most interesting to you. So let’s hear a little bit about your research. Our bodies are comprised largely of water, and your research focuses on water dynamics and links to metabolic diseases. Can you tell us a little bit more?

JPA: So when I was a surgery resident, I was on the thoracic surgery service. And a clinical observation was that a lot of the patients undergoing thoracic surgery that didn’t have any preexisting conditions — they were going for a wide resection or some . . . it’s major surgery, but they were going for surgery, And I was told as the intern that I had to keep them negative. So I had to give them Lasix and make sure that they didn’t stay . . . their eyes and nose weren’t positive. I was fresh out of my PhD, and I was like, “Why am I giving these people Lasix?” And it always bugged me that we were given the diuretics, and I didn’t understand the physiology: Why were these people producing antidiuretic hormone? Because that’s the problem. If you don’t give them diuretics, then they can develop hyponatremia, low serum sodium. And that sort of stuck with me: Why is this happening? Why is this happening?

And then I kept asking the question “Could the vasopressin be coming from somewhere else, not just the brain?” Because the explanation has been like, “Oh, everybody gets . . . the body gets stressed, and the hypothalamus produces the vasopressin.” I’m like, “I don’t know if that works out.” And I continued to follow that. And then when I came to Vanderbilt and was studying nephrology landed on polycystic kidney disease and realized, “Well, they have high vasopressin levels as well, and this is driving disease — is this all coming from the hypothalamus?” So then I started on my research, and my research career has been built initially on understanding how vasopressin works and showing that vasopressin is not just made by the brain. We were lucky enough to publish in JCI insight in 2022 that vasopressin is made in the kidney. So functional vasopressin is coming from the kidney.

The physiological relevance is what we’re working on now. But that goes to show that . . . what we’re interested in is that if each cell has the ability to regulate its own water metabolism, and water metabolism is intimately linked to glucose regulation and fat metabolism and bioenergetics, then is there anything else that we’re missing in terms of understanding how water can change our internal environment? So that’s the current focus of the lab. And again: a circuitous route to get to where we are now. But I’m incredibly excited about the work that we’re doing.

JSY: How fascinating. Well, thank you for sharing how you came upon that — just asking questions of patients in your patient care and how that really led to your research in vasopressin. Many people are working to reduce bias in the workplace, and you have advocated to eliminate the requirement of applicants to provide their pictures in their ERAS [Electronic Residency Application Service] application for residencies. Can you expand on that?

JPA: So initially I got the opportunity to be a chief resident for the Vanderbilt Internal Medicine program. And we were doing a lot of these interviews, and this was I think 2018 to 2019. And this was — we were doing in-person interviews and reviewing the files. And initially when we were reviewing the files, the way that you download the ERAS documents, the first thing that would pop up was a picture. And I would find that when we were doing evaluations, the first thing you see is the picture. And that to me just sends the . . . you have a preconceived notion of what this person is or isn’t. And I started looking into some of the data, and there’s actually data that the picture can definitely bias how you see an application.

So what we decided to do is, we came up with a more comprehensive system to evaluate applicants. We have a pretty thorough spreadsheet, like a data set that we go through and we evaluate on multiple levels. And we eliminated some of the test scores and we focus on who this person is and what their trajectory this far has been. And the whole point was trying to evaluate everybody the same way. So eliminate bias in either direction and making sure that we’re evaluating the best people for the job regardless of any other factors. So that’s encouraging.

JSY: That’s great to hear. Do you know if other institutions have also rolled out a similar policy not to look at those pictures?

JPA: I know that some do. I think it’s relatively informal so far. Some people, some institutions have been doing it for a while, and others have started adopting it. I don’t know of any formal mandate to do it, which is why we wrote that letter to the editor that got published in Academic Medicine calling for ERAS to just: let’s just do this nationwide. Because again, it’s not about highlighting someone and pushing someone else down. Just basically leveling the playing field for everybody, making sure that the attributes that we care about for physicians are the ones that are highlighted when someone’s applying for an interview. So: Not formally, but hopefully we’ll get there.

JSY: Yeah, well it’s a big step in the right direction. Thank you. Can you share with us some words of advice for those perceiving bias, either conscious or unconscious, in the workplace?

JPA: My own experience has been . . . What has worked for me is I always try to assume that everybody is doing the best they can with what they have. Period. If someone is upset for a particular reason, and yelling is what they can, then that’s the best they can do with the emotional, psychological tools and everything that they have right then and there. So me coming from the position that that is the best I can get from that person right here and right now leads me to then treat everybody with more kindness and respect. Because I don’t automatically assume that they’re out to get me. Because I think that starting there makes everything a little bit harder. So just assuming that whatever reaction is the best that that person can give you right then and there makes everything a little bit easier.

JSY: Great. I really like how you say you treat everyone with kindness — kindness and respect — which is easier said than done sometimes, but great.

JPA: Yeah, definitely. I mean, I can tell you that because of my last name. So I have four names, and something that we are discussing, right? My name is, John Paul — in Spanish, Juan Pablo — and I have two last names, my mom and my dad, Arroyo Ornelas. So my full name is Juan Pablo Arroyo Ornelas. So sometimes when I’m seeing patients, they’ll look at my name and they’re like, “What’s your name? Where are you from? You’re not from” around here.” And I tell them, “No, I’m not. And generally what I — again coming back to this “Treat everybody with kindness” is when I’m meeting a patient, particularly in nephrology, I’m the kind of doctor you don’t want to meet, right? So everybody’s going to be afraid. That’s it. So if they’re scared and I meet the patient when they’re scared, everybody, and this includes myself, everybody tends to be scared of difference. And if there’s something different in a stressful situation, of course, tempers will flare. So again, going back to the “Everybody’s trying the best they can with what they have,” I go back to the patient and I explain, “Yeah, I’m not from around here, this is this.” And I give them a little bit of background. And that always has helped.

JSY: Great. Well, words to live by: treat everyone with kindness. We have many early-career scientists who watch our program. Can you tell us a few words of wisdom, lessons that you’ve learned during your career journey?

JPA: I think one of the biggest lessons that I’ve learned is I thought in the beginning that I needed to have everything figured out and, you’ll hear this a lot, that the trajectory is linear. And you can see, so from my career trajectory, nothing has been linear at all. I started off as wanting to do general surgery or general surgeon in Mexico, and now I’m a nephrologist that’s an academic scientist in Nashville. It’s not linear.

So what I would say is that same kindness that I try to show to others in terms of they’re doing the best they can with what they have, I try to do that with myself. I’m doing the best I can with what I have. And if the best I have right now is, like, the best I can do right now is just sit down in front of the TV and watch a show, because I don’t have the emotional strength to deal with either writing the paper, writing the grants, and I just can’t. And what I can do right now is make the conscious choice of: I’m going to sit down and I’m going to watch a movie with my kids. Okay. That’s what I can give. And that same kindness, sort of bring it on myself. I think that that’s the best advice that I can give, because specific advice in terms of like, “Learn this technique” or “Learn this other thing” or when to apply for a grant — what I’ve realized with myself is that the best thing that I can do is take advantage of the tools that I have to give and that I can bring to the world. Right? So if I’m in a really good place where I can push myself a little bit harder, I will try. And then if I fail, I’m like, “All right, well, I tried.” But again, that same kindness that I try to show to other people reflected on myself.

And I think that we need to learn to deal with failure a lot in science. And from the junior faculty’s perspective, I’m not good with failure, I’m not good with rejection, and I’m always paranoid. I have terrible imposter syndrome. And all I try is like, “I’m going to try my best and be kind with myself every time that I try my best.” And that’s it. That’s the best advice that I can give. Not necessarily field-specific, but just be kind.

JSY: Thank you. That was so important for you to say, to be kind to yourself. And it sounds like you’re very introspective as well, which is really important in our field and in many other fields as well. And you also talked about resiliency, especially as a physician-scientist taking care of sick patients as well. It’s tough. So it’s important to reexamine yourself and step back when you need to. And lean in when you need to. Well, thank you so much for sharing your words of wisdom today, your experience. It’s very informative, and I think will help a lot of our viewers. Thank you.

JPA: No, you’re very welcome. I’m very thankful to have had this opportunity to talk with you and I hope I’m able to help someone with this.

JSY: I’m sure you will be able to — many, many people. Thank you.

JPA: You’re very welcome.

Interview with Neil A. Hanchard, MBBS, DPhil, National Human Genome Research Institute, NIH (elected 2022)
Interviewed by Vijay Sankaran, MD, PhD (elected 20218); member, ASCI Physician-Scientist Engagement Committee

Note: The text has been edited for readability by ASCI staff.

Vijay Sankaran: Welcome to this ASCI Perspectives interview. My name is Vijay Sankaran from Boston Children’s Hospital and Harvard Medical School. It is my distinct pleasure to have as today’s guest for our Perspectives interview Dr. Neil Hanchard. Dr. Hanchard is a Senior Investigator at the Center for Precision Health Research at the National Human Genome Research Institute at the National Institutes of Health. He received his medical degree with honors from the University of the West Indies in Kingston, Jamaica, and then completed his Doctor of Philosophy in Human Genetics from the University of Oxford as a Rhodes Scholar. At Oxford, he worked with the late Professor Dominic Kwiatkowski on genetic variation impacting the major histocompatibility complex. He then completed his training in general pediatrics at the Mayo Clinic, followed by a medical genetics fellowship at Baylor College of Medicine. He then started his lab at Baylor for several years before moving to the NIH in 2021.

Dr. Hanchard’s work has helped to define the genetic causes for a range of rare diseases, while also identifying factors that cause variation in more common diseases such as sickle-cell disease. He has received extensive recognition for his work, including being elected to the American Society for Clinical Investigation in 2022. Dr. Hanchard is currently Chair of the Genome Analysis Working Group of the H3Africa Consortium and an NIH Distinguished Scholar. Dr. Hanchard, welcome to this Perspectives interview.

Neil A. Hanchard: It’s an honor to be here.

VS: Well, great to have you. To begin with, I was wondering if you could tell us a bit about yourself, your training path, and what initially got you interested in science and medicine.

NAH: I guess I have a somewhat unusual training path compared to many in that I did my medicine, as you said, in Jamaica, which is where I’m from, which is where I grew up. And following that, I won this Rhodes Scholarship, and the scholarship couldn’t be used to do, say, postgraduate training, which is what I was interested in at that time. And so, they said, “Ycou probably need to do some research.” And I looked around for something that had something to do with pediatrics, and the available project had to do with genetic susceptibility to prematurity. And I was always fascinated by genetics and thought it really interesting. But that was really my first interaction with research at a bench level.

And so that was an opportunity that completely changed the trajectory of where I ended up being, and it was an [was able] to make the most of. And so while in Oxford, I got into genetics and I loved it. It was a great explanation for why things happened and so much more definitive. This was also around the time when the Human Genome Project was finishing. So there was all this incredible excitement about the potential to be able to dissect complex traits and other diseases. And so it was a case of really good timing and an incredible opportunity. And so that’s kind of . . . Once you’ve had the wool taken off of your eyes, you’re like,” Whoa, this is really something incredible that I can participate in.”

VS: Wow. It’s so exciting to hear about how in some ways it was serendipitous, that you encountered genetics in some ways and that took you in a new direction. Could you talk about the impact that mentors have had in your career, in shaping these different transitions, and that have helped you to shape your path as a physician-scientist?

NAH: I think I’ve had the good fortune to interact with a number of really strong mentors who are somewhat atypical in that they’re all physicians and physician-scientists, but they also all had a very clear view of what they wanted to achieve. For instance, Professor Kwiatkowski, who recently passed along, he just wanted to understand malaria and why children got malaria and died from malaria. But what was really insightful for me was the way in which he went about it. He did it with a kind of grace and kindness that, I’ve since learned, discovered, is not something you find everywhere. And so that’s something that I’ve tried to emulate in the way in which I approach my own mentorship of those who are in my lab and those who I interact with as collaborators.

And I had the same thing after I finished my PhD. I’d gone back to Jamaica for a while and worked with Colin McKenzie, who was also a PhD physician-scientist. And he had the same idea and mentality about how we’re doing these things. And then most recently while I was at Baylor, I was mentored by John Belmont, who’s another physician-scientist, again, very focused on thinking about the patients and why we’re doing this and how it is that we can actually improve things in that regard. And I’ll also say that they were the de facto mentor mentors for me as I went through. But along the way, you had the opportunity to interact with others in that sphere who gave you a different perspective and helped you to understand a little bit more about maybe aspects of it that weren’t just pure academics.

So they understood how to network or how to maneuver within academia, and when to press go, when to stop, when to go forward. And those kind of interactions and seeing others in their interactions have been really, really valuable. Some of this came through the H3Africa project that you mentioned that gave me another opportunity to work closely with mentors at Baylor — Chester Brown and Graham Martin — but also to see the other side of the world and learn from researchers who are in very different circumstances and in very different environments. And I think all of those experiences play into my current approach and the way that we’re thinking about problems and approaching them now.

VS: That’s fascinating. It’s really great to hear, and I think something that we often hear from in these interviews is the role that different mentors have had along the way, both formal and informal. And it’s really exciting to hear about how that’s helped you in your own career and in your path. So then moving to your career a bit, you have and you continue to contribute tremendously to advance our understanding of how genetic variation can impact the risk of both common and rare disorders. Could you tell us a little bit more about where you see this research field going broadly in the coming years?

NAH: I think that the primary focus of the last, I don’t know, 10 years or so has really been on the discovery side of things. We’re trying to understand associations and trying to identify genes that are, say, responsible for rare disorders. I think that we’re in this transition period where now we’re trying to understand what those associations mean and how can we pull the causality out of those associations. And part of that has to do with trying to really understand how variation has these impacts. And so that means that we have to understand the in-between of, like, here is a variant and here is a phenotype, and getting a better hold of “This variant changes something in transcription or in translation or in the proteins” and see that whole progression and how that relates to a particular disease outcome or disease trait.

So I think that as we start to understand, particularly for these complex traits, how the noncoding variation impacts regulation and impacts diseases, I think that’s gonna be the current phase in which we’re in to try and really understand. And then the big corner turn is going to be whether we can make this get a way back to the patient. And so I’m really excited, particularly for Mendelian diseases, to see that there is this kind of shift and change where people are now starting to look at like, “How can we actually treat some of these rare disorders?” Now that we have a much better understanding, it’s easier with coding variants or single-gene variants that have a really large effect upon the phenotype. But how can we then translate that into something therapeutic?

And that’s really exciting, because one of the frustrations often is that you’d interact with patients and you’d feel really chuffed. You’re like, “Oh, I’ve discovered the cause of your disorder,” and they would say, “That’s great, but what are you going to do about it?” And so I I’m really buoyed by the idea that we’re perhaps thinking more about getting this back from the bench to the bedside from a therapeutic standpoint, particularly for rare diseases. And that as we get a better handle on how the genome works, we can maybe start to make some inroads in that regard for complex diseases as well.

VS: That’s really fascinating. So in addition, you’ve been a major advocate for the need to increase diversity in genetics research. And I wondered if you could comment a bit on how we can achieve improved diversity in the field of genetics and maybe more generally in biomedical research.

NAH: I think that I’ve been fortunate enough to have the opportunity to interact a lot with folks who are at the forefront of this. And the kind of lessons that they have taught me and that I’m taking away is that we just of have a multipronged approach to this. It’s not just who we study. So diversifying the research cohorts that we interact with, who the references or the individuals that constitute the references for genome variation, for instance — that’s a big part of it. But it’s also who does the studying. So one of the big things about trying to engage communities to be a part of research is that it helps when it’s someone from their community who is doing that research.

And so there is both a community researcher part but then also the researchers themselves. And having this across this entire spectrum that we are mindful of the importance of being diverse in our viewpoint. And I think that one of the keys to that is community engagement. And I think this is where it’s not just true for genetics and genomics, but also across biomedical research; that in order to enact all of this, we’re going to need to have good community engagement — where we’re listening to how communities want to be approached, what’s important to communities, and how it is that we can work together in order to get to a point where the research we do, the medications that we give, all of these things are good for all and not just for a subset of individuals.

VS: So I’d like to change gears a bit. Many of our viewers of the series are likely to be physician-scientist trainees, including those from traditionally underrepresented backgrounds in medicine and science. So I was wondering if you could comment a bit on the lessons you have learned in your own training as a physician-scientist and what advice you might give to trainees who are watching this interview.

NAH: I thought about that, and I’ve given this some thought in the past. I think one of the things that I am acutely aware of as a physician-scientist is sitting in this kind of in-between portion, where on one hand you have scientists and science and then you have the physician and the patients. And there’s a niche group of us who sit in between those two groups. And that gives you a very valuable insight to things because it allows you to have a certain focus about what you’re trying to do and whom you’re trying to do this for. But it also brings a way in which you can actually do that, right? So I think that sitting at that interface is really key, and not to be undervalued.

The flip side of those is that there are challenges, and being in that in- between is that often you don’t necessarily get the recognition that, you don’t have the same viewpoint as, say, a scientist who is working on it. And necessarily, if you’re trying to do two things, you’re not doing quite as much. And on the other hand, you may never be a master physician because you’re trying to sit at that interface. And I think for many physician-scientist trainees whom I’ve spoken to, that dichotomy is something that they have struggled with. And I think what I’ve tried to get across to them is to try and embrace that, because it is still a valuable place to be. And it is the way in which we’re going to get from one to the other. It’s an important place to be in and not to be dissuaded from trying to sit at that interface, although it is admittedly sometimes particularly difficult.

VS: That’s really, really inspiring. And I guess the other question I’d love to follow up on, just related to what we had discussed earlier in this interview was you talked about the role that mentors have had and their generosity. As many of the trainees who might be watching this interview are thinking about “How do I identify mentors or get to know mentors,” I was wondering if you had advice there that could help them as they’re seeking that process.

NAH: I can only speak, I guess, to the kinds of experiences I’ve had. I think I’ve been very fortunate to have mentors who shared very similar ideals, particularly in terms of science and a physician-scientist type of approach to things. And that’s been very helpful for me. So I think finding your people, so to speak, is actually really important. Sometimes that can be at meetings and figuring out which meeting is your meeting, where are your people? And so identifying who your people are, who will be supportive of the work you’re doing or the approaches that you’re taking, and how you go about and think of things is something to put high on the list of consideration. But I also think that being open to being mentored outside of just your immediate supervisor is also really important: thinking about mentors who may not know your work at all, but may have useful insight about how you navigate the academic world and the kinds of decisions that inevitably come down through these kinds of efforts that need to be made, and what are the kind of pros and cons that go into making those decisions. And I found that having some of these people who aren’t my direct supervisors but who are confidants who you can run stuff by actually has been really insightful and helpful. I think the other thing about choosing a mentor is that senior people, who often have the keys to the kingdom, they are often pretty busy. And so it’s important that your mentor can have the time to be able to do this, and some people don’t have the time, and it’s not because they don’t want to, it’s just the practicalities of life.

But it’s also a lesson to not put all your eggs in one basket, right? So if you have a group of mentors whom you’re not necessarily pulling upon an extensive amount of time from one individual, you’re much more likely to get what you need through a group of individuals just because you kind of spread the same effort over many individuals.

VS: Well, this has been an enlightening and fantastic discussion. I was wondering if you could provide some closing thoughts for the audience.

NAH: I think that the things that I am in the middle of now are this idea that, particularly as physician-scientists, we are in a position to enact sea changes where sea changes need to be enacted. And that’s not a position to be taken lightly, but it is something that can be done particularly in terms of some of the diversity efforts that I’ve been involved with, but also in terms of back-to-the-bedside type of activities that, again, I feel are really important. And we are in a position to ensure that that stays as cutting edge as it needs to stay in the sense that we don’t have to do everything the same way that everybody’s been doing it for the last 50 years. But it’s important to know what’s been done for the last 50 years.

But I think there’s just incredible opportunities now, especially with the big data and data sciences that are expanding, to really have a big effect and to enact these kind of big environmental shifts that are needed, to push medicine in general, and for me personally, genomic medicine forward.

VS: Well, thank you so much, Dr. Hanchard. It has truly been outstanding to be able to chat with you today.

NAH: Thank you so much. It’s been wonderful to be here, and I’ve really enjoyed chatting.