Maya Hoptman

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.

Interview with Dr. Jose Florez, MD, PhD, Harvard Harvard Medical School,Massachusetts General Hospital (elected 2014)
Interviewed by Vijay Sankaran, MD-PhD, Vijay Sankaran, MD, PhD (elected 2018)

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. Jose Florez. Dr. Florez is the Physician-in-Chief and Chair of the Department of Medicine at Massachusetts General Hospital, a Professor of Medicine at Harvard Medical School, and an institute member at the Broad Institute of MIT and Harvard. As the department chair at MGH, he oversees over a thousand faculty members and 900 trainees, including clinical fellows, research fellows, and medical residents. Dr. Florez’s lab has contributed to numerous large-scale genomic studies in type 2 diabetes and related phenotypes. He’s earned a number of awards for his contributions, including being an elected member of the American Society of Clinical Investigation and the Association of American Physicians, as well as being recipient of the 2010 Presidential Early Career Award for Scientists and Engineers. In addition, he received the 2019 Father of the Year Award from the American Diabetes Association. Dr. Florez, welcome to this Perspectives interview.

Jose Florez: Thank you, Vijay. 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 got you initially interested in science and medicine.

JF: Sure. So I do come from a family where my father is a physician-scientist. He got his medical degree in Spain and then came to Dartmouth to get his PhD in pharmacology. And the reason that’s relevant is because during through those three years, I was born, in Hanover, New Hampshire. So even though my parents are Spanish and the family returned to Spain after he finished, I had dual citizenship, which opened the doors of being able to return to the United States for my training. But the real — not only, it wasn’t just this example — the real element was that my two sisters had special needs, and the younger one in particular was born with Down syndrome. And so I was fascinated by the idea that a change in DNA material in genetics could lead to such a variety of phenotypes, including affecting the brain.

So I was always interested in combining, understanding the way that genetics has influence on human phenotypes, particularly cognitive phenotypes. But then I was exposed to my parents’ reaction, not only from an intellectual perspective but from a human service perspective. And so the combination of service to the most vulnerable and then understanding what happens in biology to change the human condition — I think those two kind of coalesced as I continued my training into this desire to be a physician-scientist, where you have the ability to serve at the same time as advancing knowledge. So, that was kind of the nucleus from which it all came. So I did return to the US for my undergraduate training at Northwestern, and there I was going to be premed. But then there was a combined bachelor-master’s program that you could accomplish in four years as long as you had a strong research component. I joined a lab the second week of my freshman year and then got involved in research right away as an undergrad where my mentor offered me a research project my sophomore year that I took all the way to graduation. And then I learned about the existence of MD-PhD programs, stayed at Northwestern for my MSTP — and that’s how it all went, with the goal that I would become a neurologist interested in genetics. And then that also changed. Maybe we can talk about that next.

VS: Yeah, I’d love to hear more about what prompted that transition as you were thinking about neurology and then what got you sort of into the field of medicine.

JF: So the plan of course was going to be — I was going to be a neurologist who understands neurodegenerative disorders like Alzheimer’s disease and the genetic component. And there was a very strong group here, at Harvard, at the time: Dennis Selkoe and Jim Gusella and others working on that sort of approach. And so that was my interest in coming here. And then something unexpected happened, Vijay. And that is that when I entered my medical internship as a preliminary intern at Mass General on my way to become a neurologist, you come in with very low expectations about internship being a fun time or a time — sort of a tunnel from which you emerge on the other side. And I absolutely loved my internship and I really love being a medical doctor, taking care of all the problems across all the systems that affect a person. And then what I discovered on myself during that year is that I probably was more of an internist at heart in terms of my clinical practice than a neurologist. And that was confirmed once I started neurology, I did continue on.

And a few months into my neurology residency, I realized that I really missed medicine. And after some reflection and many conversations and a lot of introspection about the kind of physician I wanted to be, I decided that medicine was more my cup of tea. I finished the year, so I’m not, so as not to leave people in the lurch, but then I returned to my medical residency at Mass General a year later. Continued that, then within medicine, endocrinology was the clinical discipline that appealed to me because it was so molecular. Also, all the pathways are well worked out, it’s very elegant. And then within endocrinology, diabetes I like clinically because it is a chronic disease and you accompany people through their entire life. We haven’t cured diabetes, so we have them forever, but also many different organ systems are affected in diabetes and so that appealed to me clinically. So, I kept my clinical interest in endocrinology and diabetes, my research interest in genetics and then that led to this career in the genetics of type 2 diabetes that has taken me to this point.

VS: Wow, that’s really inspiring and fascinating to see how during all of these transitions, there’s sort of unexpected things that you learned about or that really had an influence upon you. I was wondering if you could comment a little bit on the role that different mentors have had along the way in these different career transitions or even as you’ve been making further transitions.

JF: So, I would say there’s maybe one variable that was critical for everything has been the presence of amazing mentors at every stage of the way. So I’ve already told you about joining a lab as I began my undergraduate career as a freshman. Now I had just come from Spain, I had a very strong accent, my English was not great, and this person took a bet on me and took me into his lab. And within a year of washing glassware, he said, “I like the way you work, and I would like you to start a research project. Why don’t you start by taking my course.” This is Dr. Aryeh Routtenberg, who’s now deceased, at Northwestern. “Take my course and then after you finish my course in the fall, then you can start a research project.” And then he hosted me to do essentially independent research supervised by a graduate student. But that really introduced me to the world of the lab. So critical role by him.

My PhD mentor, Joe Takahashi, at Northwestern, he was a person who was excited by his work. I remember him giving a talk, he was presenting his work to MD-PhD students before they chose their lab, and you could see the spark in his eye and how his science was something that really motivated him. And once I joined his group, he was uncompromising with excellence. Every experiment had to be — and then you have to maybe repeat it a couple of times — every paper, everything you do has to be top-notch, so it really showed me that you have to always aspire to perfection. You may not reach perfection, but at least you need to really do top-notch work and publish in the best journal. So that was great. And then during my clinical rotations at Northwestern, one particular mentor, a neurologist, opened a door that I didn’t think was open. He said  — When I was looking at what programs to apply to, I feared that the Harvard program was beyond me, it’s out of my reach and it was combined Mass General–Brigham, that one of the top-tier neurology programs in the country.

And what Dr. Vick told me was, “Jose, you need to go to a place where everyone is better than you are, everyone is smarter than you are, because that’s where you learn. It’s your peers, it’s the people around you, and so the sky’s the limit. You should apply and see what happens.” And so he kind of forced me almost to apply and then I ended up matching here at Mass General and Brigham, so that was wonderful. And then right when I was here, two people, David Nathan on the clinical side and David Altshuler on the research side, really contributed to the career that I have. David Nathan is a clinical trialist; he was at the time leading the diabetes prevention program, a major clinical trial in type 2 diabetes. Wonderful clinician, head of the diabetes center, supportive person. And David Altshuler was establishing his genetics work in complex genetics. And then being able to synergize the two, where somebody really knows complex genetics for complex human traits, the other one has clinical trial material and data, can we then do a project where the two of them work together through me, where we do the genetic analysis and the diabetes prevention program?

And so that had legs, we applied for a grant, we got our R01 together. David Altshuler was the PI because I was just a fellow at the time, and that led to our first New England Journal paper, which kind of launched the entire thing. So none of that would have happened without amazing people batting for me. And it’s continued, I mean I would say even more recently — and we can go to the next question — Katrina Armstrong, who was the chair of the Department of Medicine here at Mass General, she is the one who led me to be diabetes unit chief and the endocrine division chief, and I’m so honored to just succeed on her shoes in the department.

VS: That’s incredibly valuable insight, and just great to hear how all these mentors have contributed throughout your career. Speaking of this transition that you’ve recently made to being department chair at Massachusetts General Hospital, I was wondering if you could tell us a little bit about what prompted you to take on that role, and during this period of time, what have you learned and where do you hope to go with it as well?

JF: It’s a big question. So a number of things maybe to frame it. I guess the first thing I would say is that I never, when I started as a physician-scientist, I never envisioned that I would have sort of a career based on climbing the ladder in academic administration. I never went into this because I want to run a unit or a division or a department. It’s things that sort of almost fell in my lap, and not something that I planned or trained for, for that matter. And so when it came to the department, for example, I never wanted to be a department chair just to be a department chair. In fact, I’d received many various offers to apply and consider positions elsewhere, and I never really acted on any of them for really great institutions and wonderful places. But I did not see myself as leaving Mass General and the Broad Institute where I carry my research work to then run a department somewhere.

Now when the opportunity came at MGH, it was a little different. You know, MGH is a place that trained me to be the physician I am today, trained me to be the scientist I am today. Is where I met my wife, at Mass General. She was an intern when I was a junior resident. My four daughters were born in this hospital. And my older sister, which I mentioned briefly, who has special needs, was diagnosed with a rare genetic condition at age 44 right here at Mass General. So I have incredible institutional loyalty for this place. And now the position became vacant. And so then the question is, Can I be of service to Mass General? Can I pay back what I have received to help this institution through some really difficult, challenging times that we have in academic medicine and particularly in Boston with this turbulent matters in a number of different fronts that we are facing? And there’s a lot of uncertainty, trepidation, people who feel unsettled. And so can I be of use?

And so the first question for me is, like, What was going to happen to my research program? I’m really committed to what we’ve done on the scientific front. And one of the things that gave me comfort in pursuing and going forward is that our research and our team are quite mature. And it was really at a point where many junior faculty and people are up-and-coming could actually take large pieces of the research enterprise, and it would not lose the step. It would not miss a beat, it would just continue unabated with people who are really, really good. And so that gave me some reassurance that the field and our work would not be hindered by my taking a step aside and taking on this much larger responsibility.

And given what I thought I might be able to contribute because of my background, because of my love for the place, because of my vision, I said, well, I can just make myself available and then trust that the process will play out. And if it’s meant to be, then I will emerge as the candidate, but if somebody else is better suited for the position or for the moment: more than happy to support that person because what else do I want than the best person to take on the job of running my department? And so, threw my hat in the ring and applied and met a lot of wonderful people along the way, was able to articulate what the vision was, and then ended up where I am today.

VS: That’s really exciting. That’s fantastic to hear. And just quite a journey, and it just goes to show how much you’ve learned during your time and appreciated the institution, and your ability to give back is really fantastic. I was wondering, you mentioned the research program and I was wondering if we could just visit that for a minute. You’ve contributed enormously to our genetic understanding of type 2 diabetes and many of the related phenotypes. And you’d mentioned writing this R01 early on in your career and sort of seeing all that work kind of progress over time. Where do you see the field going in the coming years? What sorts of things excite you, and where do you see things sort of progressing?

JF: So as you know, Vijay, I think one of the most momentous occasions that you and I, probably most if not all of our audience have lived through is that in our lifetime we saw the entire sequencing of the human genome. Right? So it’s a unique, very special event in the history of humankind: all the millions of years we’ve been on earth and then all of a sudden in 2003, all of us were alive and in fact in science, and in medicine, when the entire blueprint of the 3 billion base pairs were sequenced. And that is bound to be transformative. What we don’t know is in what parts of medicine will it be transformative. And I’m relatively agnostic. There’s some people who are really into the genome hype, like it’s going to change everything we do. Well maybe, maybe not. Maybe we’re really good clinically, or maybe the genetic information for specific diseases is not really actionable because of a number of different considerations.

So of course, you are leading tremendous work, where you’ve shown in some areas where it’s already clinically useful. I think in the diabetes and metabolism field, we’re a little bit behind from hematological disorders, and I think the question is still out there. And so I am driven by trying to answer the question, In what scenarios around diabetes and metabolism will the human genome transform the practice of medicine? And what I’d like to see in my scientific lifetime is to see instances where that has been the case. Can we make the case that in this situation, genomic medicine will transform how we take care of patients? And so I think for type 2 diabetes — and this is all at this point, we haven’t proven it yet, but I think there is some legs to the arguments — there may be three areas where we might make a difference.

One is in using genetics to understand the heterogeneity of diabetes, the phenotype. Diabetes is defined by hyperglycemia. That’s a high glucose level that of course is a result of many different processes. It really is a heterogeneous condition, and it changes depending on the part of the globe and the kind of person you have in your office. And I think genetics can help at least distinguish the subtypes, the endotypes, that point to the specific pathways that lead to hyperglycemia, given as some different flavors for diabetes where you have type 2A or B or C that really are pathophysiologically distinct and that recapitulate the epidemiology that we already know is there. So I think understanding heterogeneity of diabetes, the nosology of the disease, is one. I think another one has to do with being able to use also genetic information to predict response to therapy. So pharmacogenetics is one of the big areas that we’re engaged in. And so we have 12, 13 different classes of type 2 diabetes drugs. Some of them are really good, but today we don’t make any selection based on the underlying pathophysiology. The reason the way we choose diabetes meds really has to do with a number of considerations like comorbidities, like cost, like side effects, and they’re not necessarily saying, this is the type of diabetes you have underneath and this is the one I’m going to target. So trying to use genetic information and other omics to predict who’s going to respond to what medication, I think is a way we can in introduce precision medicine. So that’s the second area.

And maybe the third one is now that we have all these parts of the genome where we know nature has told us that genetic variation is sufficient to change a phenotype in humans because that’s what we’ve done with the genome-wide association and sequencing studies, that we know that this change in DNA sequence is sufficient to give you a human phenotype. Then can we then leverage that knowledge to understand mechanism better? And so going from variant to mechanism and eventually to therapy, so it’s very laborious work that happens from variant to function to therapy, is another big, big horizon where I see we’ve been able to generate traction. We already know among the genetic associations that some of them encode targets of established diabetes drugs. So we already know that some of the diabetes drugs we use — thiazolidinediones, sulfonylureas, GLP-1 receptor agonists — have genetic evidence supporting them. So in that treasure of genetic information that we have found, there’s bound to the others that might lead to new pathways that can be harnessed therapeutically. And so that’s the kind of the next frontier for discovery.

VS: Seems like an incredibly exciting future ahead and I think there’s lots to be learned. So I’m really excited to see all that comes in the coming years. So to change gears a bit, many of the viewers of this interview are trainees who’re at different stages of their career becoming physician-scientists. And I wanted to see what advice, based upon your own experiences, you would have to those individuals embarking on that path.

JF: Yeah, so I give a mentoring talk and I close with 10 “pearls.” I don’t want to go through all the 10 here, which are along the questions that you have. So I’ll just maybe just select a few, some of them that are relevant to the conversation we already had. I would say one is to make sure that you surround yourself with a great mentoring team. And what I mean choose a good mentor, it’s not simply a good scientist, not simply a good physician, but a good person — a person who has your best interest in mind, a person who, when the rubber meets the road, is going look out for you more than to him or herself. It’s very easy to be a good mentor when everything is aligned, when your paper is my paper, when your grant is less money than I need to raise for you. But it’s a little different when maybe the interests diverge. So what is that person going to do in this very asymmetric relationship to ensure that when it comes to a decision, you are the one who thrives? And so there’s different ways in which you can gauge that, but really choosing a good mentor, making sure that you have not only your main mentor, but other informal mentors and that you’re on their radar, so they see you, I think is key. None of us can do this alone. And my experience is all based on people who helped me along the way. And there’s plenty of us who are dying to help the next generation. So that’s, I would say, one piece.

Then the other one is to not be afraid to change and not feel like you are in some sort of straitjacketed course of action based on some decision that you made when you were very young. I remember writing essays for my neurology residency talking about neuron being an amazing cell and the brain being a sophisticated organ. And then about a year into residency, I had to eat humble pie and then say, Well, maybe I’ve changed because I discovered a new thing about myself. And so if you need to change based on who you are or your circumstances or whatever else has appealed to you, then it’s okay to change. Because there’s so many things that one can do in this world, and you really are only going to be productive if you’re happy. And so you need to really get up in the morning and be excited about what lies ahead and if that requires a change for you to be able to get up and say this is what really moves me, that’s the way you’re going to be most effective. So that’s maybe another piece I would mention.

I think maybe a third point of advice would be, Always give it your best, even when you don’t feel like it, even in an area if you don’t think that that’s going to be something that’s useful. But you’re engaged in it because, I don’t know, you’re supposed to do this type of rotation or you’re supposed to engage in this particular collaboration. Always do your best so that people around you always realize that this is a person who always delivers what he or she can do regardless of what the appetite is for a particular action. And then finally, don’t fall into the trap of comparing yourself to people around you all the time. I think those comparisons are unproductive and sometimes even destructive. You don’t know the talents other people have, you don’t know the opportunities other people have, and so the only comparison to me that makes sense is when you set yourself as the only benchmark. Am I a better scientist today than I was a year ago or a better physician than I was a year ago? Have I improved, have I done better? It’s that growing through your path that really matters. And what people around you are doing and achieving is irrelevant to your own path. So maybe those are the pearls.

Maybe I’ll close just with one more. Just make sure you take care of yourself. That all of us have different ways in which we nourish our inner strength and keep us motivated. Work is a very important part of life, but it is not an end in itself. It’s a means to an end. It’s a means to discovery, it’s a means to contribution, it’s a means to a livelihood. It’s not an end in itself. So living and being fully human really requires making sure that you take care of yourself and you see work where it needs to be in the right perspective.

VS: Wow, those are all incredibly valuable pearls, and I’m sure, both myself but also even many of the people at various stages of their career really benefit from reflecting upon those. So Jose, thank you so much. It’s been such a wonderful conversation today, and I just can’t thank you enough. Thank you.

JF: Thank you.