Maya Hoptman

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 Diversity, Equity, and Inclusion 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 Diversity, Equity, and Inclusion 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.

Interview with Pamela A. Guerrerio, MD, PhD, National Institute of Allergy and Infectious Diseases, NIH (elected 2020)
Interviewed by Jennifer S. Yu, MD, PhD (elected 2022), member, ASCI Diversity, Equity, and Inclusion Committee

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

Jennifer S. Yu: Good morning and welcome to ASCI Perspectives. I am Jennifer Yu from the Cleveland Clinic, and I have here with me Dr. Pamela Guerrerio. Dr. Guerrerio is a Senior Investigator in Chief of the Laboratory of Allergic Diseases and Chief of the Food Allergy Research Section at the National Institutes of Health. Her research has focused on understanding genetic, immunologic, and biochemical determinants that lead to the development of food allergies. Her work informs how we may improve patient care.

Given the rising prevalence and severity of food allergies, her research is timely and much needed. Dr. Guerrerio has received a number of awards for her research, including the Art Trust Faculty Development Award from the American Academy of Asthma, Allergy, and Immunology, and the Presidential Early Career Award for Scientists and Engineers. She was inducted into the ASCI in 2022. Dr. Guerrerio, welcome, and thank you for taking the time to speak with us today.

Pamela A. Guerrerio: Thank you, Jennifer.

JSY: My pleasure. Can you share with us your path to becoming a physician-scientist? Was there something in particular that attracted you to this career path?

PAG: Yeah, so I grew up on a farm in Iowa, and I went to the University of Iowa for college. I was fortunate as an undergraduate to be able to do research all four years, which I absolutely loved. So when my advisor told me about a combined MD-PhD program, I thought it was just the perfect fit for what I wanted to do. So after I finished college, I came to the East Coast and did my MD-PhD at Johns Hopkins. I stayed at Hopkins to do my residency in pediatrics and then a fellowship in allergy and immunology. And that’s really when I became interested in food allergy. Growing up, I can’t say that I knew anyone who had a food allergy, and now this disease affects almost one in every 13 children. I found it just unbelievable that something as essential to life as eating could be potentially deadly to nearly 8% of children living in this country. So since then, my research career has really been focused on food allergy and understanding why some children develop this disease and what we can do to improve their clinical care.

JSY: Thank you. So can you talk to us about some of the factors that might be contributing to this increase in prevalence of food allergies and why is it that some people develop food allergies whereas others don’t?

PAG: That’s a great question. Something I spend a lot of time thinking about. I think at this point, the development of food allergy involves both a genetic predisposition as well as exposure to triggers in the environment. If you are a child and you have a parent or a sibling who has peanut allergy, you are seven times more likely to develop peanut allergy than someone with no family history. So genes clearly play a role. However, this rise in food allergy prevalence has been relatively recent, only over the last several decades. And so our gene pool doesn’t change that quickly. Genetics can’t be the whole explanation. I think there’s a number of factors in the environment that may play a role. There’s a number of studies pointing to vitamin D deficiency. We know that infants that are born in the fall and winter months are more likely to develop food allergy than infants who are born in the spring and the summer.

There’s been several studies showing that the farther you go from the equator where there’s less UV light exposure, the greater the number of EpiPen prescriptions and hospitalizations for food allergy. And that was true independent of longitude. And then I think some of the best evidence actually comes out of Australia, where they looked at over 5,000 infants and found that those who were vitamin D deficient were 12 times more likely to develop peanut allergy than the infants who had normal vitamin D levels.

And then I think there’s also a great deal of evidence accumulating that the microbiome plays an important role. We know that infants who grow up on a farm, those that have multiple older siblings, or those that have a pet — specifically a dog — growing up, seem to be protected from developing food allergy, whereas those that receive antibiotics early in life or born by C-section may be at higher risk.

There’s been several groups now that have looked more directly at the composition and function of bacteria and other microbes in the intestine of allergic and nonallergic infants. And there clearly are differences. There’s been some groups that have even taken stool from allergic and healthy infants and colonized germ-free mice, and they concluded that allergic infants are missing bacteria that can protect against the development of food allergy. So taken all together, I think there are likely multiple environmental factors that are acting on a genetically predisposed host that is leading to this rise in food allergy.

JSY: Very interesting. Thank you for sharing. For our early-career colleagues who will see this interview, do you have a few words of wisdom or lessons learned during your career journey?

PAG: I think the first thing I would tell them is I cannot imagine a more rewarding or fulfilling career. Personally, I can’t imagine doing anything else. But in terms of advice, I think the first thing I would say is to try and enjoy the process. The training to be a physician-scientist can seem long, and so I think it’s important to take each day one at a time and really try to embrace each step and enjoy it. The second piece of advice, I think, would be to try and reach out, encourage, and support one another. Science is a team sport. I see it again and again in my work, and there are inevitably going to be successes and failures. So it’s important to reach out, support one another along the way, no matter what stage of your career you’re at.

JSY: Well said. Thank you, Dr. Guerrerio, for taking the time to speak with us and for sharing your journey and your words of wisdom.

PAG: Thank you. It’s been an honor to be here.

Interview with Wendy S. Garrett, MD, PhD, Harvard School of Public Health (elected 2020)
Interviewed by Vijay Sankaran, MD-PhD, Vijay Sankaran, MD, PhD (elected 2018)

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

Dr. Vijay Sankaran: Welcome to this “ASCI Perspectives” interview. I’m 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. Wendy Garrett. Dr. Garrett is the Irene Heinz Given Professor of Immunology and Infectious Diseases in the Departments of Immunology and Infectious Diseases and Molecular Metabolism at the Harvard Chan School of Public Health. She’s also a professor at the Department of Medicine at Harvard Medical School. Dr. Garrett and her lab have focused on understanding host-microbiota interactions in health and disease. She has received numerous awards for her outstanding work, including being elected to the ASCI in 2020, and was the inaugural recipient earlier this year of the Marian W. Ropes, MD, Award given by the ASCI. Dr. Garrett, welcome to this “Perspectives” interview, and congratulations on being the inaugural recipient of the Ropes Award from the ASCI.

Dr. Wendy S. Garrett: Thank you.

VS: To begin with, I was wondering if you could tell us a bit about yourself, your training path, and how you came to study the problems you’re currently working on in the lab.

WSG: It would be my pleasure, and it’s my honor, and I’m grateful to be here today with you. I’m originally from Philadelphia. Educationally, I’ve gone on literally a northward path. I was educated in Connecticut and then moved up to the Boston area for postgraduate education, starting in around 2002. And I would say I have always been a curious person. And that’s why the path of a physician-scientist has been so wonderful and amazing and a great space for me, for which I’m grateful that I found it in my life. The “why” and the “how” questions enthrall me, and having that opportunity to realize health for individuals — and when they have disease, to participate in their care — has just been a wonderful experience and very fulfilling for me. And putting the two together, which physician-scientists are so fortunate to do, is sort of my happy place or space. I have had an embarrassment of riches in my scientific and clinical training, and that somehow ended me up in the gut, which is a complex biological space that I think informs a lot of human physiology and susceptibility and resistance to disease.

And that led me to study the gut microbiota a collection of organisms — which can be viruses, bacteria, archaea, protists, parasites, fungi — that intersect with our immune system, that intersect with our development — and that can help keep us healthy or maybe touch on diseases that I actually maybe treat some of the time, like colon cancer; and then, again, affect that system of health and disease, which makes us who we are. So, that’s what I study. I like to study at the molecular level. So what that means is I might get really excited about how a metabolite influences the function of a particular cell type in that body, and then how that metabolite, which maybe focuses or forces a certain behavior in a cell type influences organ function. So I like to get into the nitty-gritty, and I like to balance that with bringing it back to help people at the end of the day.

VS: That’s really fascinating. And could you maybe tell us a little bit more about, you know — along the way, were there particular mentors or experiences you had during your clinical training that really influenced some of those decisions that you made?

WSG: Yeah. As I briefly stated, I’ve had amazing mentors — so important — and not just one, but a network of mentors. So from undergraduate research and during my PhD years and during my MD years. So, it was a true honor to do my PhD work under the mentorship primarily of Ira Mellman, who is a cell biologist who thinks a lot about human diseases like cancer and also inflammatory diseases. I was also mentored by the late Ralph Steinman, who told me, and I still struggle with that advice, “Wendy, choose a disease!” I do listen to that need for focus, but many human diseases interest me. And maybe by him telling me to study a disease, he knew I would rebel and try to think about many. So Ralph Steinman was a mentor during my MD-PhD years. Also Jorge Galán, who imbued me with a love and a passion for the microbial world that started with Salmonella.

My postdoctoral mentor is Laurie Glimcher. She is now president and CEO of Dana-Farber Cancer Institute. She is an inspiring person, a phenomenal scientist, and working in her laboratory as a postdoctoral fellow was one of the best decisions of my life. I have also had clinical mentors that are sensational, like Charlie Fuchs, who at the time was at Dana-Farber Institute. So I have seen so many paths. I have had wonderful physician-scientist mentors, and feel so fortunate and feel deep and abiding passion to pay it forward and also to learn from my mentees.

VS: That’s tremendous. I guess one thing I’d love to just dive into a little bit more is: You’d mentioned how a lot of your clinical observations have led to many of the things you’ve been interested in, research-wise. And reciprocally, you’ve sort of had this passion for thinking about the microbiome and how that influences health and disease. And I was wondering if you could comment on how those areas of your expertise — both in sort of thinking about colon cancer and then the microbiome and host-microbiome interactions — how that sort of led together and fed your career in different ways, as you’ve thought about these areas.

WSG: A primary clinical interest is colorectal cancer, and the colon is the most densely populated microbial ecosystem on the planet, which is mind-blowing. For me, it was sort of an easy kind of thing to be curious about, to connect configurations of the microbiome, microbial metabolites with a propensity to develop colorectal cancer or to have different responses, susceptibilities to developing colorectal cancer. So that, just coming from those PhD studies, doing an internship or residency and a fellowship and then a postdoc, it just seemed to be a natural progression. But of course, when we engage in the clinical care of patients with cancer, we see a lot of complications, right? I know, I think you’re an oncologist as well. Yeah. And one area of complication or just physiological derangement that I was seeing a lot of was kidney problems, chronic kidney disease. When we disrupt the GI tract and the fluid balance of a human, the kidneys take a hit. And I got really interested in the intersections between gut microbial metabolism and kidney function. And metabolites.

So, the vast metabolites that the gut microbiota make and how they influence kidney function — and really that was because I had so many patients with gastrointestinal malignancies that I was taking care of, or helping to be part of a team to take care of, at Brigham and Women’s Hospital that were there with renal failure. I got moved a little bit into the nephrology space scientifically because it was a problem that the patients were dealing with. A lot of our patients have complications that are infectious in nature, and they receive antibiotics.

And so the scientist’s brain gets engaged with not only drug resistance, but configurations of microbiomes — what metabolites they’re making in response to those perturbations where we have to give an antibiotic to preserve life to get someone out of a tough situation. But then what are they doing? How do they affect responsiveness or nonresponsiveness to disease? We’re treating an infection with the best agent or a broad agent before we know what infection it is. What’s the infectious agent? But gosh, what are the long-term effects of that? How does that microbiome bounce back? Is it resilient? Is it in a stuck place now, and are there implications for that, how they’re going to respond to X or Y or Z therapy? And so it’s so much fun to be a physician-scientist. Every patient we want to bring to health, we want to bring them comfort, we want to show them kindness. And we’re so grateful that they’re sharing with us all their complex biology and that each patient sort of has questions for us, but they generate so many questions.

There’s so much science within that individual at play, and if we can put the right lenses on and see how we can realize that science to bring them back to health, that’s a joyful thing. That’s a discovery. That’s the motivation. And sometimes it can be a small molecule, you know? One molecule can be different, or a balance or abundance of a class of metabolites — and gosh, how do they work? And how can this make this person feel a little better, make their kidneys work a little better, make their cancer grow more slowly or make their T cells or dendritic cells act a little differently in the tumor microenvironment?

VS: That’s tremendously inspiring and really just an insightful way of viewing the opportunities we have as physician-scientists. I know it’s hard to have a crystal ball and to know exactly where things are going, but given all of your tremendous work at the interface of host and microbiome interactions, I was wondering if you could sort of think about and speculate where you see things going in the coming years and how you see the field evolving or changing, and even where you see the field kind of entering clinical medicine and clinical practice as well.

WSG: I’ve talked a little bit about metabolites today, and the dirty secret of the metabolomics field, and it’s not a secret, is we now have fantastic devices and machines that can detect a whole bunch of different stuff. And the challenge is: There are millions of metabolic features we can detect, but how do we prioritize what to study? How do we even identify, how do we prioritize what to identify? I’m really excited about what’s there, what we’re detecting — but what’s unknown from a bioactivity standpoint, and unraveling the vast wealth or tiny treasures that microbes make, either as a community or small groups. And how they push us to health or disease resistance. Or again, if we’re going to focus on cancer, how they slow growth or prevent cancers from reaching the size that we can detect.

So really excited about the metabolism space and the challenges of how single metabolites and groups of metabolites: who wins out in terms of function? We have all these inputs, but which way does the cell go or the collection of cells goes, or the tumor microenvironment, how does it evolve in response? What are those inputs that really push output? And that can mean computational approaches. That can mean computational approaches and wet lab approaches that are clever or innovative or high-throughput or model human disease better. I love the discovery, but the thing that we’re always reaching for, it’s not the stars at this case, but it’s to help someone have a good quality of life. And not just to live longer, which is good, but to live with a good quality of life.

How can we turn that knob a little bit with a huge amplitude of effect. Right? And I think that the microbiome — or I hope, right, or I think at this point in time — the microbiome and its metabolites are one way that maybe we can change the system or put someone back on a path to health or help them live with their disease longer. Maybe that’s the aspiration. Live well and live longer with that disease.

VS: Wow. Yeah. I know, that’s really inspiring. And I guess just related to that, it seems like that’s an area that hasn’t received nearly as much attention as many other areas in terms of thinking about, especially, cancer pathogenesis or other aspects. Many times, there’s been a lot of work on sort of targeted therapies or other things, but not necessarily thinking about how the microbiome contributes. So do you think that there might be a whole set of new therapies or other things emerging from these kinds of studies?

WSG: I sure hope so. I embrace therapies that look for targets within the microbiome, for one. I love that idea. If we can think about ways — adjuvant is such a tricky word for us, us oncologists — but if we can think about ways in which we can use the microbiota to help therapies work better: totally onboard for that. If we can think about how we can . . . These ideas get complicated, but how we can change our exposures, that is, diet or what we consume, or certain molecules that are part of our dietary pattern — that leads to a shift in the microbiome, which in turn helps drugs work better. I’m all for that. We’re not there yet.

VS: Yeah. But it’s an exciting future, and I think there’s so much possibility, it sounds like, really.

WSG: Because we have to bring rigor, we have to bring robustness. We have to be mindful of our preclinical models and think deeply about how to improve upon them. So we can ultimately translate safely to humans, you know. And I think we all need course corrections sometimes along our path or within our fields; we need standards, times for reflection. This field of microbiome studies or microbiome sciences, just like other fields, sometimes hits those points. Especially in the cancer biology space or the cancer space where microbiome science and cancer come together. And that’s fine. It’s an opportunity for people to think more deeply. And that’s always welcome.

VS: Absolutely.

WSG: Get our heads together, whether it’s in clinical medicine, like having a team think about a problem, going before a tumor board, or having just a group of collective, the collective think — that’s good. And that’s good for science, and it’s good for patient care.

VS: Well, I want to change gears a little bit. Many of the viewers of this series are likely to be physician-scientist trainees, including those from traditionally underrepresented backgrounds in medicine and science. And I was wondering if you could . . . I know you talked a little bit about your mentors and their influences, but I was wondering if you could comment on some of the lessons that you learned in your own training as a physician-scientist and what advice you might give to trainees who are watching this interview.

WSG: Okay: You belong. You belong, you belong, you belong. If you are a gut microbiome person — and that’s good, you don’t have to be — but I’m going to tell you, diversity is good in the microbiome. It’s associated with health. So the more differences in opinion, the more diversity of perspectives, the better, the richer, I think. So, I think when I was a trainee, people would say to me things that I didn’t quite appreciate. And what I’m speaking about is the importance of representation. And I think since becoming a student, I’ve truly grown to understand and appreciate the impact of representation. I think when I was a student, something I didn’t understand is how meaningful it is to me now to see that there are physician-scientists that maybe are a woman for example, or self-identify that way.

And I think I didn’t appreciate the importance of that, to see someone that you identify with in some way from one side of the lectern versus the other, or one side of the attending versus medical student sort of divide: that is deeply meaningful. So I would say, as a student I might not have fully understood, since I trained a long time ago, or somewhat of a long time ago, how important representation is. But I have grown in my own sort of personal space to appreciate how important representation is. And so, I’m much more comfortable now saying, you know, “I’m a woman physician-scientist” than I would’ve been when I was applying to MD-PhD programs.

The other part is the belonging piece. I don’t know how to instill in people they belong. I think medicine and academic medical biomedical sciences have become more inclusive since when I was a trainee, but we’re not there yet. We need to still work on that, and just tell yourself . . . Be kind to yourself and tell yourself you belong, that you’re on this beautiful path, which I really do believe it’s not always an easy path, but this is truly a wonderful life. It’s a life of service. It’s a life of wonder. It’s a life that is joyful, and a life as a physician-scientist that I am so grateful for. And one that is full of opportunities for gratitude.

VS: Well, this has been an incredibly enlightening and fantastic discussion, Dr. Garrett. Would you be able to provide some closing thoughts for the audience, or are there other things that you just wanted to mention that I didn’t have a chance to ask about?

WSG: I would just say that if you are curious, that is a beautiful attribute. Not every moment is easy, not every day is easy, but I deeply believe in how fulfilling the physician-scientist path is and how many opportunities there are within that arc or rainbow that is being a physician-scientist. And we need physician-scientists. Science is so important for the future of clinical care. It doesn’t mean we don’t need people that do implementation science, but we also desperately need basic scientists. It doesn’t mean we don’t need computational scientists, but we still need physician-scientists that do wet bench research and preclinical models. So: You belong, maintain your hope, and this is a beautiful life.

VS: Well, thank you so much, Dr. Garrett. It has been truly outstanding to be able to chat with you today, and I really appreciate this. Thank you very much.

WSG: Thank you. It’s been a privilege and an honor.