Month: January 2024

Interview with Sean Agbor-Enoh, MD, PhD, NHLBI, NIH (elected 2023)

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 Nana-Sinkam: I’d like to welcome everyone to ASCI Perspectives. My name is Pat Nina- Sinkam. Today, I have the pleasure to have as our guest for ASCI Perspectives Dr. Sean Agbor. Dr. Agbor is Laboratory Chief, NIH Lasker Clinical Tenure-Track Investigator, NIH Distinguished Scholar, Lead of the Laboratory of Applied Precision Omics at the Division of Intramural Research at NHLBI. He’s a Lead Investigator and Director of the Genomic Research Alliance for Transplantation, Adjunct Associate Professor of Medicine, Lung Transplant Program, at the Johns Hopkins Hospital. He’s also the recipient of the 2021 James T. Willerson Award in Clinical Science. Dr. Agbor has dedicated his career to understanding genetics and genomics and how they are used to elucidate the pathogenesis and progression of diseases such as pulmonary arterial hypertension, COVID-19, and graft dysfunction post–lung transplant. In particular, his laboratory is really focused on cell-free DNA for the development of liquid biopsy biomarkers to inform clinical decision making in diagnosis, prognosis, and disease monitoring. Dr. Agbor, I’d like to welcome you to “ASCI Perspectives,” and I’d also like to congratulate you on your recent selection to ASCI. Thank you so much for joining us.

Sean Agbor-Enoh: It’s truly a pleasure. Thank you for having me.

PNS: So I would like to start out by maybe just asking you if you could share a bit with the audience your path or your journey to become a physician-scientist, and in particular, how did you decide to focus your line of investigation on transplant immunology?

SAE: So, I come from Cameroon; it’s in Central Africa. And this is relevant to why I became a physician-scientist. It’s in Central Africa — if you think about the map of Africa, where you come from Africa: Ghana, then Africa makes the turn to start going south. Right where it makes the turn, that’s Cameroon. Right where it makes that turn, that’s Limbé, where I grew up. Now, why is that relevant? On the other side of the Atlantic Ocean there is the highest volcanic mountain in western Central Africa, Mount Fako. I grew up there. Black volcanic sand. So part of the beaches are black. I tell you, it is . . . if you have time, go visit; it’s a very beautiful site in the world.

Now so when I was growing up, never in my mind thought of even becoming a doctor. We were surrounded by chemicals, and next to that area is SONARA [Societé Nationale de Raffinage], which is a petroleum company. So we grew up really poor. So you can imagine the rich kids in the area that you go to school with, their parents work for the petroleum company. So the dream for most young men growing up there, surrounded by rich volcanic soil, seeing money through petroleum, was to go towards chemical engineering or such fields. Medicine was the last thing in my agenda, truly the last thing. And so after high school I said, I’m going to find opportunities to go to the UK to study petroleum engineering, of course. And then my father of course didn’t have money to pay for me to go and said, well, if I give him about two–three years, he will raise that money. Now, he said, “In the meantime, don’t stay home. Why don’t you just apply to go to medical school while you’re waiting to go to the UK to start the petroleum engineering?” Most of my friends after high school went and did that. And so I went to medical school. I wrote an entrance exam. It’s a competitive — you write it, you get selected, you go. So I went there. But the first two years of my medical school was terrible. Grades? Oh, don’t even get me started. You need to see my transcript, because I was just . . . For me, it was just a place holder.

And then eventually I figured out my father: that was a trick, and I am going to just be in medical school. But I did . . . My thought was always petroleum chemicals until in my fourth year of medicine; it’s a seven-year program. We went to do an outreach activity for the WHO. When we went to this village, we walked about eight to twelve miles through the dense equatorial forest to get to these villages. We were giving Mectizan, which is a drug that WHO was giving at the time to treat filariasis. In one of the villages, we met the chief of the village, and he had a son. That son was about . . . They don’t have birth certificates there, but you could estimate somewhere between 16 and 20, and he was stuck in bed. When he sits up, he would get short of breath. Then when he lays down flat, he feels better. That just astounded me because I’m used to heart failure or other conditions that cause shortness of breath that you get better when you sit up. This child felt better when he lied down, Of course, I couldn’t figure it out until during my fellowship, many years later at Johns Hopkins. And I figured out what that patient had and indeed wrote a paper in one of the ATS (American Thoracic Society) journals about that experience: this idea of shortness of breath which gets better when you lie down. But that is the case that led me to, number one, be interested in medicine, that I could make a difference in a patient. Unfortunately, that young child died while we were there, and you can imagine, it hits you. I said, well, maybe if I knew a little bit more, I could help that child, that young man. And the young man died then. Then it just goes, the question is, what did this young man have?

The rest, I’ll tell you, it’s practical, it’s really history. After medical school, I got an opportunity, through the Fogarty International [Center], to travel to Georgetown and did a one-year research internship and just loved it; and so I decided to do a PhD. At the time, I did a PhD in biochemistry, molecular biology, and trying to clone a gene for malaria. And that got me interested in genomics. And so a PhD comes, residency at Hopkins, and everything. But then I started asking the question, how do I then apply what I have learned to address a major problem? During my last year of residency and my Chief year, I had an encounter with a lung transplant patient, and I started learning about the condition: the idea that lung transplant definitely saved lives. These patients would otherwise die if you do not get a lung transplant. So it’s a beautiful story. I loved it. However, unfortunately, within only five, six, seven years of transplantation, half — 50% — of these patients unfortunately die because of complications of rejection.

That’s number one. Number two, it amazed me that this transplantation is one of the only medical conditions where you take an organ from a different person, i.e., a different genome, and put it in another person, a different environment, and that genome needs to make a decision. The genome could adapt in that new environment and survive, or if the genome fails to adapt, it unfortunately would be rejected. So it marries, then, some principles of rejection, some principles of genomics that I learned in graduate school. And this idea of trying to ask why to address a major problem. There is the path to lung transplantation and to lung transplant research.

After my fellowship, I was literally barbecuing behind my house. I can tell I have many kids. We were barbecuing one Sunday, and I got a phone call, “Hey, my name is Hannah Valentine. I’m from Stanford. I want to set up a genomic research lab.” Guess what? In transplantation. I’m there, wait a minute, where is this coming from? And so Hannah Valentine called me and said, “Can you come from Hopkins to the NIH, join me at the NIH, and set up this?” And a wonderful mentor, just a wonderful person. And that interest just married together. And that’s where the pathway, the path of this is. The path has been traced way early in Cameroon. But that’s where I finally ended up, and that research has been ongoing since then.

PNS: That’s an amazing and inspiring story. And I’d like to use that to kind of delve into the question about your actual . . . the research that you’ve been doing. As you know over the last probably one to two decades, liquid biopsies have been a real focus for many, many investigators. And in many diseases, the liquid biopsy is considered almost the holy grail for diagnosis, for treatment decisions, prognostication, and so forth. Yet when we look at liquid biopsies, every group has their compartment of interest that they like to focus on, whether it’s microRNAs, proteins, extracellular vesicles, circulating tumor DNA. Yet your group has focused on cell-free DNA. Can you share with the audience a little bit about why cell-free DNA? What have you learned from the work that you’ve done with cell-free DNA, and how do you see cell-free DNA perhaps being the holy grail for liquid biopsy in understanding human disease?

SAE: Thank you very much. So cell-free DNA is one of the measures of liquid biopsy, but overall the concept truly amazed me while I was thinking about where in genomics I should approach transplantation. Because a lot of these models, you can approach them using genomics, microRNAs. Vesicles have a big content of nucleic acid. You could approach them in that. But why cell-free DNA? And I would give a plug about that and then talk a little bit more, in a perspective about all the other biomarkers, of my thoughts about how they would come together. So cell-free DNA are short DNA fragments that are released when cells die or they’re undergoing regeneration, and that ends up in body fluids. It could be blood, urine, CSF, and all that. In plasma, for example, in the healthy patient, there’s a 100 billion — this is billion with a B — 100 billion fragments of cell-free DNA, all coming from all over your body. That intrigued me. And this is DNA: DNA drives everything that each of your cells does. And it seems like this DNA, not only is your DNA sequence coming, but the epigenetic landscape of that cell where the DNA is coming from, that epigenetic fingerprints are preserved on cell-free DNA. Therefore, it felt to me that with just a little bit of plasma from a patient, could I sample that patient and trace what is happening in different organs in your body, almost providing a whole-body molecular scan of what’s happening?

So transplantation felt like a good place to start, because in transplant, again, you have genomic admixture. You have the genome of the donor, and you have the genome of the recipient. So in addition to these epigenetic fingerprints that I talked about — and I’ll come to that in a little bit — you have also single nucleotide polymorphisms. The transplant organ has DNA sequences or single nucleotide, but that are distinct from that of the recipient. So with plasma, therefore, you could use those SNPs, or single nucleotide polymorphisms, to track cell-free DNA coming from that allograft. And if DNA is released when an allograft cell dies, therefore, the amount of allograft-derived or donor-derived cell-free DNA could guide you into what is happening to that allograft.

So cell-free DNA then offered that opportunity. It is also indeed quite stable. They’re wrapped around nucleosomes. As you know, nucleosomes are these eight-mer proteins that are dense in positively charged amino acids like lysine and all that. So their positive charge on everything almost spells it — they’re so resistant to endonucleases and everything. As I tell my students in the lab, you can take cell-free DNA, literally put it on a stone, get a hammer, and hit it. It does not break down. So, a very stable molecule, very abundant in plasma. You can use plasma to almost derive what is happening in several tissue all across the body. And we started the story in transplant, and we showed some really key principles: that number one, it is sensitive. It can track injury coming from that organ, indeed. Indeed. It can pick up that a patient is getting rejection two to four months before the patient shows any clinical symptoms or before the biopsy becomes positive. That, I’m telling you, that just wowed me.

And so early detection — and we have studies now trying to figure out if early detection and early treatment of rejection guided by cell-free DNA would improve lung transplant outcome. As I mentioned earlier, these patients die within five to six years, half of them from complications of rejection. So those studies are ongoing. But then we backed off and said, “Wait a minute, could we test and try to validate some of these principles in other conditions, such as pulmonary hypertension, COVID-19?” And that story seems to be the same: that with these conditions, you can not only use this to detect complications early, but you can also use this to re-stratify patients for poor outcome. Like in pulmonary hypertension, you can re-stratify patients for transplant-free survival. Patients who will need a transplant or will die from their disease — you can identify them years in advance. With COVID-19, at the time of patient admission, you can re-stratify the patient to see which patient will need ICU care and therefore maybe do interventions a little bit early. So that is what cell-free DNA can do. This idea that it’s a stable marker in plasma, that you just noninvasively get a blood collection and you can sample different things happening in that organ. Now you can define tissue injury in pulmonary hypertension and COVID-19, for example. These are nontransplant conditions.

However, how do I know that there’s injury from the heart, injury from the kidney, injury from the liver? This is simply because while the DNA sequence in your entire body is identical: your heart pumps, your lung breathes and it’s an immune organ, your liver does all kinds of metabolism, your kidney does excretion. So how can the same DNA with the same sequence orchestrate such distinct functions in different organs? The reason is because each organ has epigenetic fingerprints that are specific to that organ. Those epigenetic fingerprints — DNA methylation, histone, chromatin footprinting — they are preserved on cell-free DNA. Therefore, if I get plasma from a patient, I scan the epigenetic fingerprints on cell- free DNA. Could I therefore assign the organ or tissue which is producing that cell-free DNA? So that’s the technology that we then transfer from, to test the principles that we learned in transplantation to study pulmonary hypertension and COVID-19 and a few other diseases that would be coming up. So in summary, that’s been the love for cell-free DNA.

Now, however, the other biomarkers in the field, the non-liquid biopsies, such as the microRNAs, the extracellular vesicles, I think these carry similar information, but I think each of them have some small added advantages. Now we have people specializing in different areas. My hope is that coming very soon, as we have learned about these molecular approaches, that at some point we’re having now the technology, huge computing, people doing machine learning, big data — that it is time for marriage, where, say, a cell-free DNA person gets, collaborate[s] with a microRNA or extracellular vesicles, and we see how these two approaches combine, better informed how to triage our patients and how to select appropriate treatment or re-stratify them. Or even better, further understand the mechanism of what disease is happening. And again, the long game would be that these approaches would help us identify what is happening in disease in a way that we do not need to go get biopsy samples from an organ. But could we identify what is happening looking at just blood and looking at these different approaches?

PNS: So I’d like to kind of just extend on that and ask you to perhaps reflect on and maybe even predict what you see as the next series of important scientific questions to ask and to hopefully answer. So for those early-career investigators who are thinking about perhaps a career in transplant immunology and maybe even studying lung transplant — recognizing that we’ve made tremendous progress, but as you said earlier, the outcomes in lung transplants still tend to lag behind some of the other solid-organ transplantation. So what do you see really as those important scientific questions that we need to be asking and answering to start to narrow some of those gaps when it comes to lung transplantation outcomes?

SAE: So lung transplant truly has a need. I’m telling you, if there’s a branch of medicine that is in real need of a physician-scientist, lung transplant is. For most other diseases, you have to wait years before you see patients with poor outcomes. While it’s unfortunate for the patients, the idea that you can get some of these outcomes early and you can track patients over time to get these outcomes, is that an opportunity to understand what is going on in these patients? Let me be a little bit more specific. In all solid organ transplantation, the lung and the small bowel have the poorest outcomes. It’s not exactly clear why, but there’s several hypotheses, and that’s what we are all working on.

It so happens that these are organs that have just truly big lymph nodes. If you think about the small bowel, they have pouches underneath the gut epithelium. The lung has all kinds of lymphoid organs as well in there. Second, they’re exposed to the environment. They’re exposed to all the particulate pollutants and everything that is available in the environment. You have that. They’re available, they’re all microbial particles and all that. You have that. And then third, these patients are immunosuppressed. What a cocktail to trigger inflammation! In the lung, we’re looking at things like cell-free DNA. Lung transplant patients at baseline, whatever you can define as baseline: when they’re not having rejection, their cell-free DNA is about tenfold higher — tenfold higher — than in heart transplant patients. Cell-free DNA is a measure of baseline injury. Just think about how much lung injury these patients have compared to patients who have heart transplant. So there is true opportunity there to understand this interaction, what the environment contributes, and what inflammation contributes and the underlying autoimmunity or now allograft immunity — because you have an allograft, so you call it that — it’s indeed autoimmunity.

But this interaction between these three components that a lot of focus is on. Lung transplant provides that basic field. It feels to me that understanding those basic principles that drive these baseline injury patterns in these patients will help to better understand what is going on and how we can stop it. Not only that, not only that, we have also seen that by studying things like environmental particulate matters in lung transplantation: Would that help patients with asthma? COPD? Think about the gut, inflammatory bowel disease. The principles that you would learn from these rare diseases such as lung transplantation, these principles are potentially broadly applicable in other conditions beyond transplantation.

So this is a call to the young physician-scientists that are coming. That, in my mind — pick a problem that is passionate to you. Something that you wake up and you think about; something that in your mind, you believe is a problem. And then that devotion towards that mission to improve outcomes, at least that’s mine, is to put a dent to improve outcomes in those patients for whom lung transplantation is the only cure. That’s my mission. And now rejection and early detection is an approach that I’m taking now. My hope is we can make a dent. But do that, pick a problem that is passionate about, and then harvest that passion. As a physician-scientist — I’m telling you this idea of taking a problem that you see in clinic, bringing it to the lab, diving deep into it, looking at mechanisms, identifying interventions, going back to see how you can improve these patients: this is the holy grail of medical practice.

This passion I hope I can transmit to my colleagues who are coming up and thinking about this. It is just something that, I will tell you, if you develop that and pick the right thing that’s good for you, that you feel so strongly about, it is hard to not love it. And so it’s a field — we do have challenges: trying to find grants, trying to find dedicated time for research, trying to find so many components that we need to do this work. It’s hard. It’s really hard. There are lots of mentors that have done it. My people say — I’m from Cameroon, as I said earlier — If you walk on the shoulders of giants, you can see further. So mentors are just amazing. I would advise that they look for mentors.

Someone that truly, you can tell, that they just want you to succeed. They don’t have to be in the same field as you, but they can guide. And then my hope is that you can find those components, a mentor, a problem that you’re passionate about, and then the two together, bringing those two together, it would be likely that you’ll find the resources and the time to do it. Then call me back and tell me if you do not find joy just doing what you’re passionate about. So that is what I would leave as advice to the junior physicians coming up.

To big groups like ours or the group that I’m so excited and I’m so honored to belong and to come join: ASCI . . . I think we have started advocacy already. We are right at the forefront of advocating what we think is going help promote this track of physician-scientists. My hope is that joining ASCI, that will be something that I could also lend a hand. And as physician-scientists, we have to all continue that advocacy to try to see how we can make the bed easier for these colleagues of ours that are coming up with so much passion to do this. If we can give them the tools and help them to integrate their life and their work such that they can both live and do this so passionately, then I think we would be moving in a straightforward path.

So let me summarize that. For my colleagues coming up: passion, passion, find the problem with passion. Find a mentor or mentors. And truly a big shout out to ASCI, for an association like this, for advocacy. My hope is that we all can join in this advocacy to try to provide the microenvironment that will just make this feel richer. And it ends up benefiting everyone: the patients; the government, because we help save money and we do all these things. So why not?

PNS: I think that’s a fantastic note to end on. I certainly speak for all of ASCI in saying how much we appreciate and how fortunate we are to have you as a member of this organization. Your commitment, your passion, your scientific excellence are beyond reproach. And we wish you the very, very best. We’ll be looking for great things from your group. You’re certainly a role model, and we hope that there’ll be many more who follow in your footsteps. So I really want to thank you on behalf of all of ASCI for just taking the time to speak with me today.

SAE: No, thank you. I’m truly honored for the opportunity to give my perspective as well. Thank you.

PNS: Thank you so much.

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.