Brendan Lee, Ph.D, M.D, featuring Ling Qin, Ph.D.

In this special episode celebrating the 40th anniversary of the Journal of Bone and Mineral Research (JBMR), host Ling Qin, MD, PhD, sits down with Brandon Lee, MD, PhD, Chair of the Department of Molecular and Human Genetics at Baylor College of Medicine and Director of the Center for Skeletal Medicine and Biology. Dr. Lee reflects on his remarkable career, from pioneering discoveries in skeletal genetics to advancing genomic medicine and translating rare disease research into life-changing therapies.

The conversation explores the evolution of skeletal biology over the past four decades, the power of human genetics to unlock new scientific insights, and the importance of mentorship, collaboration and embracing emerging technologies. Dr. Lee also shares the personal experiences and mentors that shaped his career, discusses the impact of ASBMR on the skeletal research community and offers inspiration for the next generation of physician-scientists.

Transcript

SPEAKER_00 0:00

So, hi everyone. Today's interview is a part of JBM 14th anniversary celebration. So I'm the host. My name is Lin Ching, and I'm a professor of orthopedic surgery at the University of Pennsylvania. It's my real pleasure to welcome Dr. Brendan Li, a true pioneer in the field of medical genetics and skeleton biology. Dr. Li is the chair of the Department of Molecular and Human Genetics at Baylor College of Medicine and the director for the Center for Skeletal Medicine Biology. As a physician scientist, Dr. Li has dedicated his entire career to unraveling the genetic mechanism underlying development in disease. He has performed the groundbreaking work identifying the causes of skeletal dissipations and translating genomic discoveries into therapeutic realities. His research has fundamentally shaped our understanding of how we build and repair bone. We are very honored to have him with us today to share his insights. So, Dr. Li, I would love to hear a bit about your backstories. How did you actually find your way into the world of skeleton biology and real disease? Is that a straight line or is there some twists and turns another way?

SPEAKER_01 1:22

Well, first, Ling, thank you so much for taking the time and this wonderful honor for by the ASBMR to participate in this great celebration. So, you know, my path is, I think, a typical one. I am a true example, much like you and many of our peers and colleagues of uh immigrant story. You know, our country is made great by immigrants. And I arrived as a five-year-old, literally in New York City, by chain migration. Um, and as often is the case with uh immigrant parents, you know, we I've very much focused on um science and medicine, partly because my parents expected me to. Um, I think I was very lucky that that really became my passion as I, you know, grew through school. I uh did my training in uh my MD and PhD in New York, and um really by luck, and I think uh luck is a very important part of all of our professional paths to to have the opportunity to see something exciting and to really grasp it. And I think that's where I um in my uh PhD training uh at the State University of New York Downsite Medical Center as part of a seven-year Baumed program, I uh discovered genetics. Uh, did not really know what it was because I was an undergraduate organic chemistry major, but it was clear that genetics and molecular biology was going to take over the world. And this was in the late 80s. And I think my my career has been driven by that. You know, I have been a geneticist at my core. Uh, and uh, as a geneticist, I early on tackled the question from my PhD times of, you know, what are the basic causes in genes that cause human skeletal dysplasia? And paralleling that sort of path, I focused on, you know, how understanding these genes impacted human development and eventually common diseases. Um, not surprisingly, a lot of this work was uh driven uh by technologies. And again, I think, you know, when you I think about my career trajectory, um I started in the late 80s during my PhD uh embracing molecular biology, trying to clone genes, which was sort of a chemistry experiment. Uh it was really hard to do, um, but then evolved with the field, and I think that was another important lesson to embrace the technology to apply those to the big question. Then it became sort of how these genes impacted developmental biology, a phase of developmental biology and studying structural birth defects. Um, and then really with the explosion of technologies like next generation sequencing and genetic engineering, um, went deeper as the field did in terms of thinking about mechanisms of disease, how these genes affected signaling, and ultimately, uh, which is the deliverable, uh, using this information to uh inform therapy, as we focus on, and especially as a geneticist, um uh really also going back to the human and and embracing things like genomic diagnoses. How can we bring this knowledge to patients first, both in diagnostics, because that's often most tractable, and then eventually um uh therapies. So I think uh I've been very lucky, you know, having lived the immigrant dream in terms of having the great opportunities, in this case in science and medicine, and traversing a path that over the past three and a half decades have been um a mirror of how technologies have transformed our field in skeletal medicine in biology and more broadly.

SPEAKER_00 5:02

Oh, I have been knowing you for like uh 20 years. I don't know you come from New York City.

SPEAKER_01 5:08

Yes. It's good to know that you're I am an adopted Texan now, though, when I landed in Texas over 33 years ago.

SPEAKER_00 5:16

Yeah. So um when you look back at your body of work, uh is there like uh common threads or golden thread that ties all together? I'm curious if you have any scientific philosophy on my site. You think that defines your approach of science?

SPEAKER_01 5:36

Yeah, and again, I I would say this is where I uh the approach or the overall um theme has been driven uh by the excitement when I started my career of the explosion around human gene discovery. And and from that I learned early on that understanding human genetic disease as a driver for discovery uh is extremely powerful. Granted, it was really hard 30 years ago. You know, we knew maybe 50 human disease genes. Now we know over 5,000. But that theme of humans actually tell us what's important is so powerful. Uh, and especially rare disease, because rare disease um is a big effect size. It's almost like thinking about when we study mice, why do we use mouse as a model? Because effect sizes are quite big on an inbred genetic background. Well, human disease is like that. You're looking at rare variants with strong effects, and that immediately tells us those pathways are important. And so I think that is a theme. Now, certainly, humans are a great genetic model for hypothesis generation. Um, they never want to breed when we tell them to, though. So they're not very good experimental models, although it's that's changing. Um, and this is where, again, leveraging the abundant preclinical models in our field has been so important. But I would say um I've been lucky in terms of thematically to always go back to a human, and this is the great honor of being a physician scientist, to always go back to the human to test whether what we discover in cells and preclinical models um are relevant. You know, I focused very much in my career on translation, and we discussed many things that are possible. And I think without going back to the human, whether it's the individual or cells or tissue, um, we don't know whether those discoveries um translate with a big effect size. And I've I've often said, um, you know, preclinical models tell us what can happen. Uh, humans tell us what's important and what will happen. So I do think that that has been very much an overall um approach that has been woven throughout my career.

SPEAKER_00 7:46

Yeah, so just uh echo that a little bit. My background is a PhD. So while I'm doing study, I start from like cell culture and mouth models. It's convenient and I'm always fascinated by the mechanism we got from like cell culture and mouth models. But your work really gave me another thought that I have to think about like the clinic. I have to think about the translation. I have to think that what I found in the animals, that when it's the same in the human, whether it can be translated into therapies. So your work is really inspiring to me. Thank you. So yeah, so you have done some very incredible work, but I assure there's some personal highlights. So if you can just pick one or two moments, whether it's being like a specific discovery or just a patient success story that you're absolutely proud of. Can you share with us?

SPEAKER_01 8:48

Absolutely, absolutely. I I would divide, you know, what I when I look back at my career, what what I've been most proud of into two categories. I would say those things that involve science and those things that involve people. Um, I think science-wise, um it it there there were, I there's in there is no one favorite because I've had the great opportunity to work on so many different things. I've often said as a geneticist, I have a license to be on focus. I follow where the genetics takes me. Uh, but certainly in the first phase of my career during my training, it was so exciting to be part of the first teams to clone important human disease genes. You know, as I said back then, cloning a gene was really hard. And I would say I still think back to when I was a trainee and we cloned the type 2 collagen gene and showed it was the first, you know, human gene defect in in a chondral dysplasia. Uh, that was like landing on the moon. It was, you know, something that was 1980s? Yeah, it was in the late 1980s. And it's funny, I I joke with my trainees. Um, now you can do my PhD thesis in two two hours, but but back then it was really hard. Um, but it was very exciting in terms of sort of the first human genetic forms of of short stature and dwarfism. I think shortly thereafter, you know, sort of using similar approaches, cloning the fibrillant, including parts of the fibrillin gene and associating it with Marfan syndrome, that was really again an ex example of you know uh such an exciting discovery because it was just wasn't done frequently. As I said, there were very few human gene disease correlations.

SPEAKER_00 10:24

I think when I move forward into my individual reminder that at that time I was in high school, so we don't even know about like a sequencing or cloning of this concept in our text. Absolutely are so important, uh, it's a fundamental for the power study.

SPEAKER_01 10:44

Well, and similarly, when I uh started my independent lab, um with collaboration and good fortune, I think timing is everything, you know, the important transcription factors that regulated development being identified, uh like runks 2 and other patterning transcription factors like LMX1B. And again, I was able to leverage some of this outstanding work to make correlations with key genetic disorders like clidocranial dysplasia and nail patellus syndrome and many others, but to begin to now expand on not just the commonly expressed genes, which were drip that which drove the candidate gene approach, but now genes which were uh expressed in small amounts, but really powerful in regulating those matrix proteins, like those transcription factors. And that very much, I think, was another highlight of my career. I think the transition occurred when I sort of matured as a scientist to start thinking about these processes of how they impacted um common disease. You know, I've been a big believer that rare disease informs common disease, but that there was not a lot of proof of that. And I think sort of the decade after that, when we began to look at osteogenic imperfective, and you know, that was another great, you know, um, you know, period when we cloned some of the first recessive OI genes and some of the studies that led to an explosion of work by so many people on identifying genetic um conditions that informed on what regulated quality and quantity of bone. And that's been so amazing. And and some of the signaling pathways, you know, um, the the themes of matrix to to to cell signaling that was informed by OI, um, things that you would not have expected. Uh, I one of the things that still shocks me today that is that the most important and powerful wint ligand in bone is WIP1. And we could barely see it. And only human genetics would have identified that. As you know, you would have never even thought about WIP1 as important without human genetics. And it's still a big question. So I think those are certainly highlights. And now it's about genomic medicine, how we can take technologies to help patients uh make you know make diagnoses as well as genetically informed therapies. You know, we we've been lucky enough to take this all the way to treatment with some of our work on anti-TGF beta in Hawaii and gene therapies actually for osteoarthritis. Um, you know, another area of my work of which is is now involving skeleton for the past decade has been gene therapy. And and now um some of that are in phase two clinical trials. So it's been a wonderful link. I would say the highlight has been not necessarily any single things, but at how each of them reflected um the evolution of uh science in our field. I would I would also say then it's the people part. Probably the greatest um uh you know reward has been the great number of colleagues and trainees. You know, I've been so fortunate to have trained close to 100 individuals, postdoctoral fellows and graduate students, and um they are the ones who have achieved all of this. And you know, I have always prided myself on mentorship uh at a broad level, but not just not just my own trainees, but fellow faculty, you know, both in my department and outside of my department, uh, and and individuals I learn from. I mean, we are the products of just greats in our uh uh scientific giants in our field. I think some of these these individuals have been um you know uh interviewed as part of this series, and and uh I really have learned from them. So it's the people part I probably enjoyed the most. And uh I have to say that's been so important.

SPEAKER_00 14:32

Well, just as you know, that's uh you have been a role model for me in the past 20 years. So I have seen you that as a Chinese immigrant uh can grow into such a big figure doing such a semi-to uh uh important research in the field. So I think 20 years ago that I think I can somehow maybe I can be like you.

SPEAKER_01 14:56

You've done even more, you've been unbelievable. I think so so many of our colleagues have been so, you know. I think uh we don't do science in a vacuum. I think we all work together and inspired by each other's work.

SPEAKER_00 15:09

Yeah, yeah, yeah. That's right. So thanks. Uh so um maybe you can also tell us that so whether there's some kind of uh people or event that will be most impactful in your research career, because as just we just said, uh science is not a solo journey.

SPEAKER_01 15:28

Well, I I have to say, so I look back on this whole path, there's the first, of course, it has to be my family because they've sacrificed so much. You know how much our field demands of us. I mean, it's a it's not a job for us, it's a passion, it's an avocation, but it still takes a lot of our time. And so there's no question I could not have done this without my wife and and her support all these years. Um, in terms of professionally, I would highlight probably three individuals that taught me an enormous amount. The first was Francesco Ramirez, who was my PhD mentor, and who brought me into the world of collagen and human genetics. I knew, as I said, very little about this field. And he, you know, took a took a chance on me. I literally walk into his office as a as a medical student saying, I want to do research. And I I I barely understood what the word molecular biology was. And I I very much learned from him independence. You know, I think the idea of driving your research forward uh uh in and and being uh able to lead a project, he gave me great opportunities to lead a project, even as a graduate student and great it great freedom, you know. Um, I think that in that way it informed my approach to management, which is not to micromanage people.

SPEAKER_00 16:44

You were like an MD PhD student at that time, right?

SPEAKER_01 16:48

Well, actually, I I was a BAMD program, and then I went entered medical school as part of that, and I actually didn't do MD PhD. Uh, in my first year of my MD, I missed research, and then I joined the PhD or the MD PhD late because I missed missed research so much. So it was sort of an indirect path. But yes, I was MD PhD but entered in medical school. Oh I see. So Korea was amazing. And and then I think the second great person was David Remoyne, who I have to say, uh he's past now, but he's a father of human skeletal dysplasia. I learned from him, you know, the idea that you should always uh embrace the newest technologies to answer your question. And also I learned from him in enormous generosity. He was so great at giving credit to all of the people around him. Um and that was so important. Uh that really was a reflection of him and his leader. And finally, Art Bodet, Art, who was my mentor here at Baylor and the previous chair before I became chair, um, very much showed me about the diversity of science. I mean, I was lucky enough to work on so many areas, not just the skeleton, but all aspects like inborn era and gene therapy. And he very much was a scientist and a renaissance man in that case, of studying so many different areas. Um, and he also built this great department. I think that environment is so important. Being in a place that is supportive is key to being able to achieve your goals. So I would certainly highlight those three individuals.

SPEAKER_00 18:23

Yeah, the mentorship is always important. And right now you've been great mentor for so many people. I'm sure your students will say same thing about you. So yeah, the last part is that's uh um how about like uh SBMR? That's uh you know that JBMR is a journal for the SBMR. So what kind of role SBMR has played in your career? And does it be personally to you? And how about the community influence your career paths?

SPEAKER_01 18:57

Absolutely. I I have to say that you know I've had the good fortune of working in many areas, so I've been part of many scientific societies, but I view the ASBMR as one of my two true homes, so to speak. Um, my the home for all of the skeletal work that I do. And I've had interactions in many societies, but I would say first scientifically, the ASBMR hosts and has always been the model of, I would say, the most robust science that at least I see is out there in the skeletal world. So uh there's no question it's the premier scientific venue for presenting science. That's not to say there aren't, there isn't great science in other areas, but I would say in terms of what we do, there is there is no comparison. I think the other is, as you know, I'm a physician scientist. The SBMR is such an unbelievable venue for having clinicians and basic and translational researchers make. So that's so important. Um, where you hear about interventional clinical trials all to all the way to very basic structural studies. I think that, again, there are not too many societies that are like this, certainly in our domain of the skeletal field. So there is no question in terms of the type of science that's presented. And I would say the last and most important, whether you're a trainee or senior or mid-career faculty, is because of the interactions, you know, the networking, it is so important. Um, being able to listen to other people, interact with other peers, um, is where you get ideas. Uh, I I've often said there's no such thing as a new idea. We we often hear about ideas from from other domains and remake it into something innovative. And I think that um that it's a meeting where, because it is so diverse scientifically in our area, that it is uh the networking opportunities are are absolutely wonderful. So, you know, for me, it has been how I've gotten to know individuals like you and and others and learn from all of you. And I think that um it it is so essential in in professional development. And I certainly view it as one of my scientific homes. It's it's uh certainly a meeting I go to every year for for now many decades, and um um no matter how you know science has evolved.

SPEAKER_00 21:19

Yeah, I think that I think last year or the year before last year, you got to the Extinct Award at SBMR, right? Well, that was a great honor, yes. Yeah, it's a fantastic moment. That is an awesome meeting I went to for the past 20 years.

SPEAKER_01 21:35

So that's uh I look forward to seeing you every year there.

SPEAKER_00 21:39

Yeah, it's uh I I look forward to seeing you and as a scientist and have a great talk uh over there every year. It's uh yeah. So thank you so much for your time and this is the insightful discussions.

SPEAKER_01 21:54

Thank you.