Transcript of the November 2023 Florez/“ASCI Perspectives” video

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.