Transcript of the October 2023 Garrett/“ASCI Perspectives” video

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.