Crohn's Disease and Creeping Fat with Dr. Jeong Hyun

On this episode of Scrubcast, Dr. Jeong Hyun, an assistant professor in the division of pediatric surgery at Stanford University, discusses his journey becoming a surgeon scientist. Hyun’s research is focused on Crohn's disease and how strictures develop in the intestines. Shout out to MD/PhD candidate Khristian Bauer-Rowe, who he collaborated with on the September article in Cell looking at the role of creeping fat and CTHRC1+ fibroblasts.

The episode also touches on Dr. Hyun's personal interests, including his unexpected love for country music, which he developed while working in Kansas City. The discussion concludes with Dr. Hyun acknowledging the uncertainties in research funding and the importance of vulnerability and resilience in both personal and professional life.

Rachel Baker: [00:00:00] Welcome to Scrubcast, where we take a closer look at the research happening at Stanford University's Department of Surgery. I'm your host, Rachel Baker. Today we're speaking with Dr. Jeong Hyun. Welcome to the show.

Jeong Hyun: Thank you for having me.

Rachel Baker: Thank you for joining us. It's great to have you here. You graduated from Stanford's General Surgery residency program before during your pediatric surgery fellowship.

At Children's Mercy Hospital in Kansas City, now you are back as an assistant professor in our division of pediatric surgery. What was it about your rotations at Packard that made you say, “this is what I wanna do with my career.”

Jeong Hyun: Well, I think careers are a little more, they're not linear, right? Sometimes there's branch points you don't think about when you're starting to project out where you're gonna be in the future.

Right? And so during my pediatric surgery at Kansas City, I was basically offered a job to stay in Kansas City. Um, and I thought that's what I was going [00:01:00] to do. But for various reasons, that fell apart sometime in my second year, which is a little late for the job search, honestly, when you're a pediatric surgery fellow.

So I just sort of switch paths and so then I went and interviewed at a bunch of places and I remember I was sitting at my kitchen table and I was staring at these two contracts in front of me right To go to, I would say their community, um, orthopedic surgery programs. There, no, there's no real, no research component involved in it.

And after a while you just. You have to stop training, you have to get a job, you know, and, and the numbers they put in front of you right, are like monopoly numbers compared to what you are earning as a resident, a fellow. And so you're just looking at this like, I should sign one of these places. There's just something in the back of my mind where I always.

Where I thought my career was gonna go involved a heavy research component. I did three years with Dr. Michael Longaker, who's probably the premier surgeon, scientist in the country doing translational stem cell research. And I always thought [00:02:00] that my academic profile would be in that basic science translational lab component.

And once you sort of differentiate down the clinical pathway, it's really hard to get back on the academic pathway. And so I was just kind of looking at this thing. And I knew from Dr. Dunn who had reached out that Stanford had a possible opening, but I needed to do a critical care surgical fellowship.

That's what they were looking for. But it required another year of training. And so I'm just kind of looking at, it's like, do I need, wanna do another year to get to where I want to go? And in the end, that's the decision I made. Right. And it's not that, you know, had I had the job offer in hand, I had to go apply for it.

I had to interview for it. I had to go through all the different rounds of interviews, but in the end, I became what I wanted to be, which is a surgeon scientist, you know, and a surgeon scientist right now, especially with the headwinds that are sort of everywhere, it's really difficult. I think one of the few places you can do it is at Stanford, [00:03:00] because of not only the research milieu, which Stanford is the worldwide leader in research in, if you want an expert in anything sort of collaboration, they're there on campus.

Right. It's such a huge advantage, but not only that, like it's the backing of the Department of Divisions. The backing of Dr. Hawn, who really stresses how important it is the backing of Dr. Dunn, our division chief, you know, who also stresses research is part of what it means to be a surgeon. There's not many places around where that sort of backing is there, where it's not just clinical focused, which I understand is very important part of being a pediatric surgeon, but.

That more than anything is what made me want to come back to Stanford because honestly, I can't really think of another place in the world where I'll be able to do what I'm can do here. And so it was worth it for me to take a little more circular route to come back. To honestly the niche that I'd already sort of developed under Dr. Longaker over at Hagey [00:04:00] Pediatric Surgery Research Building. I knew people, I knew how things worked, and so I think that's a huge advantage. And again, most importantly, to have the departmental division, structural backing for why research is important is more important than even any dollars they give you because if you're just strictly clinically based and then research is sort of something on the side.

You're never gonna have time. You're never gonna have enough effort. You're never gonna have enough backing when the things that people care about are how many appendixes you take out or blah, blah, blah. How much billing you do, right? And so that's why I came back to Packard. That's the whole Stanford research umbrella. How people treat it here is what brought me back, honestly.

Rachel Baker: Absolutely love it and I'm so glad that you did. One of the things that you specialize in is inflammatory bowel disease or IBD, which encompasses a group of chronic conditions, but the two big ones are Crohn's and ulcerative [00:05:00] colitis. Am I pronouncing that one correctly?

Jeong Hyun: That's correct.

Rachel Baker: How did you become interested in IBD and what are the big differences between these conditions?

Jeong Hyun: So that's a great question. So inflammatory bowel disease, when you learn about it in medical school, it often is presented as like Crohn's and ulcerative colitis are sort of kind of almost the same, but they're not.

But there's sort of a generalized sort of pattern to how these patients present. And I would say I became interested in inflammatory bowel disease because for me, these conditions strict almost to the heart of. What it means to be human, right? Like there's nothing quite as social or even the things that give you the most enjoyment of life as in eating, right?

It's to share a meal with someone is almost like you are now part of their family, right? Like it's a very communal thing [00:06:00] and there's few things that can give you. The best joy and the best connection with someone was sharing a good meal with somebody. But these patients, oftentimes every meal can be a time bomb for them.

They never know what's gonna set off their condition. And so. For me, when I see these patients, especially pediatric patients and this, they often present very much in their teenage formative years, where going out with their friends to get a pizza or things like that is so important and to see them suffering from just being.

So afraid of what they can eat their diet and control. And so you very much get this sort of almost inflammatory bowel disease subtype of these patients. They're very type A because they have to be, they have to control almost every aspect of their life.

Rachel Baker: Mm-hmm.

Jeong Hyun: Because you never know what can set off their inflammatory bowel disease conditions, stressors that we wouldn't normally even think of.

Environmental cues, especially diet. And so they become this very type A almost [00:07:00] nervous—understandably--and they're just thin, especially the teenage years, they fall off a growth curve. It's one of the first things you see in IBD in pediatric populations is in teenage years, they start falling off the growth curve.

And so, for me, this condition is one that we as surgeons, to alleviate human suffering, to bring people to wholeness, is one that we absolutely need to treat. And as for your second question about the difference between all ulcerative colitis and Crohn's disease. Ulcerative colitis is a little bit different because it's just limited to the mucosa and usually just to the colon and rectum itself.

And in a sense, there is a surgical cure. If you take out the rectum and the colon, you can pretty much take out the disease. Right. It's not going into the small bowel now. Nobody wants to get their colon taken out, right? But the difference here is Crohn's disease, it can happen anywhere from the esophagus down to the anus.

Let's say, [00:08:00] a stricture happens, which is a narrowing of the intestine. And so as a surgeon, you have to cut that out in order for food and liquid to pass through. Very often these patients will recur, especially a pediatric patient who gets diagnosed in their teenage years.

They have a lifetime of this disease, right? And so, mm-hmm. There's population studies that say 50% of these patients stricture again within the first 10 years. You get diagnosed as a 16-year-old, you can imagine how many repeated surgeries could happen in their lifetime. Every surgery that comes in after the first surgery is more dangerous due to scar tissue.

And then at a certain aspect, you can't cut all that bowel out and not have severe consequences for nutrition, for growth, for just your wellbeing as a person. And so honestly, ulcerative colitis is. An awful disease, but I have a special empathy in my heart for Crohn's disease patients because there's no guarantee that any of this will ever go away in their entire lifetime.[00:09:00]

And so that's why I especially concentrate on Crohn's disease. These patient populations really strike me as someone who needs a lot of.

Rachel Baker: Thank you for that explanation. I have a lot of friends who I met in my chronic pain class who have Crohn's, and I did not understand exactly what they were going through, but, so that's really helpful.

This past September, your lab published a study in Cell, we will put a link in the show notes for our listeners. It specifically looked at Crohn's disease and the role of creeping fat.

Jeong Hyun: Yes.

Rachel Baker: Which sounds, for lack of a better word. Creepy.

Jeong Hyun: Yes.

Rachel Baker: Does it actually like creep through your body?

Jeong Hyun: Yeah. So, um, that it's a great description, honestly.

So, creeping fat is this phenomena that pretty much only happens in Crohn's disease. So the medical jargon is path, which means if you see it, the patient has Crohn's disease, right?

Jeong Hyun: And so what happens is [00:10:00] you have to get the blood supply to the bowel, right? And so the blood vessels come up. And the scaffolding around the blood vessels and lymphatics and all those things is.

Basically fat. It's sort of the buffer to get it up there. And so usually the intestine is a round tube and there's this layer, thin layer fat that just kind of enters in at the bowel and just sort of interfaces there. Now, Crohn’s disease has this very unique phenomenon where the mesenteric fat basically starts growing up around the intestine itself, and so that's why they say it creeps, it's happens slowly over time.

And the fat. If you feel it in your hands, and that's a unique perspective we have as surgeons, becomes harder than normal adipose tissue where you know, we all have a little bit of excess. You can feel it. It's soft, right? It becomes hard. And quite often, in fact, most of the time, the most diseased part of patient's Crohn's disease, the intestine is associated with creeping fat.

The intestinal stricture formation that is pretty. Unique to Crohn's disease is almost always associated with this creeping fat. [00:11:00] And so as surgeons, we were always kind of taught when you have this intestinal stricter that you need to resect, you go back off into normal tissue where the fat isn't creeping anymore, right?

And so for a longest time we just sort of thought of it as a marker of disease process and didn't really sort of pay attention to it as a possible mechanistic explanation for why these patients have intestinal strictures. Well, for me, that didn't make any sense, right?

Like, something's not there just because it's there, right? Usually it's involved in something, and it's very specific in Crohn's disease that the most disease tissue has the most creeping fat. And I think there's been a lot of research in the past generation where we know now that fat is not inert.

It's very metabolically active. There's a lot of inflammatory components, immune components that are involved in fat. And I think we've all heard from the latest diet fats [00:12:00] about how like, you know, there's a certain type of fat that's not good for you, and that's true, right? There's metabolic activity in certain kinds of fat that are very harmful for you, right?

And so for me, it didn't make any sense that this was just sort of a bystander. And so that's why we specifically started looking at it in terms of are there things within the creeping fat that cause intestinal stricture formation? And a stricture is basically a scar. Just like if you have a cut on your skin, right?

And there's healing in there and there's tissues called fibroblasts that come that deposit extracellular matrix cause that area to sort of thicken up.

Rachel Baker: Mm-hmm.

Jeong Hyun: Basically in the body, a scar happens and pretty much kind of the same area everywhere. It looks a little bit different depending on the three-dimensional architecture of where you're at.

But in the heart, after a heart attack, a scar forms, right?

Rachel Baker: Mm-hmm.

Jeong Hyun: In the liver, you've heard a lot about fatty liver. The liver becomes hard, right? Like these are all scar formation. And so for me, an intestinal stricture is a scar [00:13:00] formation. So where are these fibroblasts coming from? We know that there's fibroblasts in fat.

They become quite metabolically active, and so that was a hypo hypothesis. There had been a lot of research about what's called bowel fibroblasts, where mm-hmm fibroblasts within the intestine itself could possibly be doing an inflammatory bowel disease, but no one actually looked into the creeping fat itself as a mechanistic explanation.

And it's funny, I talked recently with a worldwide expert in Crohn's Disease who, who was an invited speaker and his lab per us we're like a, a, a piece of gum on his shoe of the empire of his, he's a worldwide expert. He's so many papers and he's won awards and he'll continue to win many awards and he will.

He's made the lives of Crohn's disease disease patients better. But I was showing him his research and he just started kinda laughing. He was like, “you know, I have to admit.” And he's a gastroenterologist. He said, “I have to admit that I threw, we threw the fat away when we get the samples. 'cause we didn't think it was important.”

Now that's purely [00:14:00] because gastroenterologists and surgeons have a very different view of this disease, right? As gastroenterologists are medical people who typically treat inflammatory patients, they see them differently. They have a longitudinal view of them. Oftentimes it's symptom management, different anti-inflammatory drugs, biologics that they're prescribing. Gastroenterologists are often doing scopes to get samples of biopsies to see how their diseases are progressing. But that's very different from a surgeon who's actually putting their hands on the intestine, putting their hands in the creeping fat and seeing how that feels. It's qualitatively different. And so I think that gave us an insight that. And the majority of inflammatory bowel disease research is done by gastroenterologists medical professionals, not usually surgeons. Yep. And so I think that gave our lab a little bit of a unique insight into how this could be different.

Rachel Baker: I mean, Hagey Lab loves a fibroblast.

Jeong Hyun: They do. They do.

Rachel Baker: So the fibroblasts that you looked at were the CTHRC one [00:15:00] plus

Jeong Hyun: positive.

Rachel Baker: Okay. Um, and then the yap taz, which I actually, I've heard about that one before because of Khristian. So thankfully that one was not out of left field for me. So you focused on these two specific fibroblasts and signaling pathways.

Where do you go from here now that you know that it is in fact the fibroblast?

Jeong Hyun: Yeah, so I, I specifically like to praise Khristian Bauer-Rowe, who we both know. He is an MD PhD student from MIT who has a very special way of thinking about disease process. And he's not only that, he's one of the most compassionate, kind people I've ever met, right?

And he has his own journey in terms of inflammatory bowel disease and why it's important to him. But this all started because he wanted to make a difference. In inflammatory bowel disease. He had this unique mouse model that basically pheno copied creeping fat intestinal stricture, and that's, it was completely unique in the field.

There's no mouse model before that actually did this thing. That's [00:16:00] awesome. He came up with it. That's awesome. And so we kind of teamed up and started this process, you know, right in the smack, in the middle of the pandemic. The whole journey led to the discovery of the CT HRC one positive fire blasts, which are from the fat itself, and basically migrate towards.

The bowel from the outside and then start migrating towards the bowel inside, right? And so it's very much. Changing up the paradigm of how we think about inflammatory bowel disease. 'cause a lot, most, in fact, all inflammatory bowel disease, very much focus on inside out, right? The mucosa, the microbiome of the bacteria that are in the intestine diet, those things that are inside the intestine.

Causing inflation to come out towards the bowel. You, once again, you asked about a difference between Crohn's disease and ulcerative colitis. Crohn's is full thickness of the bowel, whereas ulcerative is very much limited to the mucosa.

Rachel Baker: Mm-hmm.

Jeong Hyun: And so. We think mechanistically of why Crohn's disease presents with strictures and ulcerative class usually doesn't is because that full [00:17:00] thickness sort of inflammation that makes sense.

And for whatever reason, that activates these fire blasts for the creeping fat itself. And then they start to migrate. Cause a whole host of dysregulation of intestinal stem cells scar formation, which is why. Our hypothesis showed a cell paper. Yeah. That this is why these strictures are forming in association with creeping fat.

And what we show is that the location of these things are very important. They seem to be located around blood vessels. This, um, really isolating the niche of how and what these cells are talking to.

Rachel Baker: Mm-hmm.

Jeong Hyun: And then, yeah, there are some very specific things that we saw within how they interact with the gap task pathway, which is one of the.

Basically three main ways that fire blasts sort of interact in terms of how they form scars. You know, PAs was another big pathway that they, you know, they talk about. And so there are basically these, uh, specific either small molecules or things that can inhibit the gap test pathway. And now we can start to [00:18:00] focus on, and then I think the big question is why do these things activate, right?

Rachel Baker: Hmm.

Jeong Hyun: There's clearly some sort of inflammation mechanism. Link between the two. Otherwise it's, I mean, it's inflammatory bowel disease, right?

Rachel Baker: Mm-hmm.

Jeong Hyun: But one of the interesting things that we've found and has been observed in Crohn's disease is that despite the absolute explosion of anti-inflammatory biologic drugs over the past 10, 20 years, and you can't escape it, right?

If you turn on the television, you'll see. 15 to 20 commercials asking your doctor about, you know, Skyrizi or whatever, you know, and the reason why is these drugs are actually really good at controlling the inflammatory symptoms, inflammatory bowel disease, like that's gotten a lot better. There's gone are the days where you see a patient that's just been hammered by steroids, you know, with the steroid side effects, right?

These biologics are quite good, but what we've seen is this spike. Really tamping down the inflammation, the [00:19:00] fibrosis has kind of remained the same.

Rachel Baker: Mm-hmm.

Jeong Hyun: There's the same stretching. So, at some point the mechanistic signals and YAP has a mechanical sensitive signaling pathway. We're not saying in fibrosis is inflammation independent.

The gastroenterologists hate it when we say things like that. We're not saying that, but at, at some point the fibrosis almost decouples from the inflammation and that if you even, even if you stop the inflammation, the fibrosis keeps going, right? Mm-hmm. And so you need a class of therapies now to look at the fibrosis aspect of inflammatory bowel disease.

Unfortunately, there are none in the market. There's no antifibrotic drug on the market at all. It's the great untapped potential of medicine right now in that. You can look at almost any disease and say it's a fibrotic disease, right? Cancers are fibrotic. Heart disease is fibrotic liver disease, which everyone's looking at is fibrotic, right?

And so there's this big opportunity there for us to kind of get in that. And then the ultimate holy grail [00:20:00] is what is the cause of all this, you know? Yeah. Can we. What actually stimulates Crohn's disease. And then that pretty much starts to unlock autoimmunity. Right? Yeah. And so whoever solves that will be, you know, in Oslo somewhere, getting the Nobel Prize.

Rachel Baker: Yeah, definitely and I'll bow at their feet.

Jeong Hyun: Yes. And there's a lot of patients who are waiting for that to be discovered. Uh, we just wanna play our very, very, very small part in that. And especially for us, our next step is to try to, now, now that we've, uh. Mechanistic target to step into that space and possibly develop some sort of therapeutic that can really stop this fibrosing aspect of Crohn's disease.

My goal, which is really ironic as a surgeon, is I wanna make Crohn's disease a non-surgical disease. We need to make it to the Crohn's disease patients no longer have to undergo laparoscopic or laparotomies to get bowel resections. That should be [00:21:00] our goal because any surgery that we do as surgeons needs to be curative,

Rachel Baker: Mm-hmm.

Jeong Hyun: And this is not a curative surgery. There's oftentimes subsequent surgery. So that is our sort of overarching goal of what we really want to do in the future.

Rachel Baker: Awesome sauce. Love it. Well, that sound means that it's time for our lightning round. On each episode of Scrubcast, we ask our guests the same three questions.

And the first one is, who is a surgeon you admire and why?

Jeong Hyun: I think for me, like the surgeon I admire the most is, is a guy named Shawn St. Peter, who's over at Children's Mercy in Kansas City. He's a, he's a surgical chief over there. And the reason why I admire him so much is he, so he basically started clinical trials in pediatric surgery.

Before him, he, we weren't doing clinical trials in pediatric surgery at all. So when he was starting his research and he's got an empire now, he just found the rigor of [00:22:00] how we as pediatric surgeons do it wanting and that we were just sort of doing retrospective prospective stuff. But when nobody was saying, okay, we need to do this, like the adults.

Jeong Hyun: We had to enroll a bunch of people, double-blinded placebo, what is the best, right? And Shawn was the one who did it and made it widespread. And not only that, he's such a good surgeon. He is such a good surgeon, and he's a normal person. Right. And honestly, I, maybe I should say less, but like the normal part of being a, a great surgeon is decoupled sometimes because of what it takes to get there. But he's a genuinely nice human being who I like hanging out with who has interest outside of the OR. And so for that, I don't know how he has enough time in a day to do all the things he does, but that's why I really admire him.

Rachel Baker: That's a special person. I like that. I'm gonna have to look him up. Uh, the second question is, what is the best advice you have [00:23:00] received in 10 words or fewer? I'll count

Jeong Hyun: failure is inevitable, but failing is not.

Rachel Baker: Ooh, six. Very nice.

Jeong Hyun: So I really think when you go into a, in the surgery field, we offer in a field of very high performance individuals and true failure in which you set a goal, you reach your cart for oftentimes, as you're going early, especially early on, you're never used to like, because you we're people who, if you set a goal, you typically achieve it, right?

Rachel Baker: Mm-hmm.

Jeong Hyun: But there will be times in your academic career, in your personal life where you truly, truly fail. Like there's no way to sugarcoat it. You just mm-hmm. It's just a failure and that is inevitable. We're all human beings. We should have the grace to treat ourselves and see ourselves as human beings.

And we should have the grace to treat other people as human beings. 'cause nobody knows what each other are going through, right?

Rachel Baker: Yep.

Jeong Hyun: But failing total failing is not inevitable. You just have to get up. [00:24:00] Keep going, and oftentimes one of the best things you can do is share your vulnerabilities as a person, as a surgeon, as a colleague with each other, because too often we're ashamed to let people know where we are weak because everybody has been there and it's does no good that everybody thinks around them.

Everyone is superman and superwoman because that's just not the case at all. We have all the things that we are going through internally as a person, as a family, as a surgeon. As a colleague and so, um, yeah. Um,

Rachel Baker: oh, I love that. I'm gonna put that one on the wall. Thank you. The final question is really fun: What is your preferred or music?

Jeong Hyun: Yeah, that's a great question. Um, so one of the interesting things, um, that I developed in Kansas City was, um, um. My wife when she was in Madison, Wisconsin, really loved and got into country music.

Rachel Baker: Okay.

Jeong Hyun: Like  the Zach Brown Band and things like that. Yeah. And [00:25:00] so what your girlfriend, fiancé, wife, likes you like if you're a sponge.

And so we had this Nigerian surgeon named Tolu [Oyetunji]. Big, gregarious Nigerian, great surgeon. He also loved country music,

Rachel Baker: Oh my gosh.

Jeong Hyun: And so it would be hilarious 'cause the two of us operate. We just turned on the Pandora country music station and you see this big Nigerian surgeon and me, this Asian American guy singing along the country music in the OR and it was like very incongruous scene and people were very confused by it.

But I'll listen to anything. I usually don't turn on country music anymore because I don't want. You know, my trainees or whatever to feel a certain way about it. But I just, uh, I, I, I kind of love it, you know, and that's sort of my little, little secret thing.

And also any Taylor Swift is, is great.

Rachel Baker: Oh, absolutely. Have you listened to the new album?

Jeong Hyun: I have, yeah. It's, it's very propulsive. I, I would say it's, has a [00:26:00] lot of energy.

Rachel Baker: Yeah, a lot of energy. I liked it a lot. Well, it has been a pleasure chatting to you, but before we go, one last question. What is next for Dr. Hyun?

Jeong Hyun: That's a great question. I think there's some uncertainty there, right? Like right now, and we won't, don't need to get into any specifics. There's a lot of headwinds with research right now in the United States. Absolutely. And especially sort of the assistant professor level is I think, the most vulnerable.

Honestly. There's certain timeframe that you need to be. Um, independently funded, have a certain track record of research and

Rachel Baker: mm-hmm.

Jeong Hyun: Yeah, it's difficult. So I would say working hard to kind of continue the momentum of our sell paper, but just because you accomplish something in the past doesn't guarantee success in the future, and so we're gonna just continue to work hard to build on what we have.

But as I said. Nothing is guaranteed. So you just have to kind of live each day doing what you can in the moment and then knowing that there are certain things you just really can't control. I can't control global health [00:27:00] policy. That's not what I can do. So you can get frustrated, but you have to also give yourself some grace to realize that you're living here now and you have your friends, your family, your health, and that's all you can kind of ask for, but just kind of move forward every day.

Rachel Baker: Absolutely. Okay. Well, I look forward to seeing you in the OR and in the lab. Thank you so much for joining us.

Jeong Hyun: You are welcome

Rachel Baker: …and thank you to our listeners for tuning into this episode of Scrubcast. Until next time, stay sharp.

If you like Scrubcast, we hope you'll tell your friends and subscribe wherever you get your podcasts. Scrubcast is a production of Stanford University's Department of Surgery. Today's episode was produced by Rachel Baker. The music is by Midnight Rounds, and our chair is Dr. Mary Hawn.