Hello Friends 👋
In this episode of the Incubator, Betsy Crouch and David McCulley interview Dr. Wendy Chung, a leader in clinical genetics and child health research. They discuss her journey into genomics, the challenges faced in her career as a physician scientist, the importance of early mentorship, and her research interests, particularly in congenital diaphragmatic hernia (CDH). Dr. Chung shares insights on the complexities of genetic disorders and the need for innovative approaches in treatment and diagnosis. She discusses her experiences with newborn screening and the evolution of genetic screening for rare diseases, emphasizing the importance of advocacy for children's health research. The conversation highlights the impact of patient stories in research and concludes with personal insights into family activities and the importance of maintaining a balance between work and personal life.
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Some featured manuscripts from Dr. Chung :
Ziegler A, Chung WK. Universal newborn screening using genome sequencing: early experience from the GUARDIAN study. Pediatr Res. 2024 Oct 26. doi: 10.1038/s41390-024-03647-w. Epub ahead of print. PMID: 39455856.
Ziegler A, Koval-Burt C, Kay DM, Suchy SF, Begtrup A, Langley KG, Hernan R, Amendola LM, Boyd BM, Bradley J, Brandt T, Cohen LL, Coffey AJ, Devaney JM, Dygulska B, Friedman B, Fuleihan RL, Gyimah A, Hahn S, Hofherr S, Hruska KS, Hu Z, Jeanne M, Jin G, Johnson DA, Kavus H, Leibel RL, Lobritto SJ, McGee S, Milner JD, McWalter K, Monaghan KG, Orange JS, Pimentel Soler N, Quevedo Y, Ratner S, Retterer K, Shah A, Shapiro N, Sicko RJ, Silver ES, Strom S, Torene RI, Williams O, Ustach VD, Wynn J, Taft RJ, Kruszka P, Caggana M, Chung WK. Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions. JAMA. 2024 Oct 24:e2419662. doi: 10.1001/jama.2024.19662. Epub ahead of print. PMID: 39446378; PMCID: PMC11503470.
Qiao L, Welch CL, Hernan R, Wynn J, Krishnan US, Zalieckas JM, Buchmiller T, Khlevner J, De A, Farkouh-Karoleski C, Wagner AJ, Heydweiller A, Mueller AC, de Klein A, Warner BW, Maj C, Chung D, McCulley DJ, Schindel D, Potoka D, Fialkowski E, Schulz F, Kipfmuller F, Lim FY, Magielsen F, Mychaliska GB, Aspelund G, Reutter HM, Needelman H, Schnater JM, Fisher JC, Azarow K, Elfiky M, Nöthen MM, Danko ME, Li M, Kosiński P, Wijnen RMH, Cusick RA, Soffer SZ, Cochius-Den Otter SCM, Schaible T, Crombleholme T, Duron VP, Donahoe PK, Sun X, High FA, Bendixen C, Brosens E, Shen Y, Chung WK. Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants. Am J Hum Genet. 2024 Nov 7;111(11):2362-2381. doi: 10.1016/j.ajhg.2024.08.024. Epub 2024 Sep 26. PMID: 39332409; PMCID: PMC11568762.
Austin ED, Aldred MA, Alotaibi M, Gräf S, Nichols WC, Trembath RC, Chung WK. Genetics and precision genomics approaches to pulmonary hypertension. Eur Respir J. 2024 Oct 31;64(4):2401370. doi: 10.1183/13993003.01370-2024. PMID: 39209481; PMCID: PMC11525347.
Ziegler A, Carroll J, Bain JM, Sands TT, Fee RJ, Uher D, Kanner CH, Montes J, Glass S, Douville J, Mignon L, Gleeson JG, Crooke ST, Chung WK. Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder. Nat Med. 2024 Oct;30(10):2782-2786. doi: 10.1038/s41591-024-03197-y. Epub 2024 Aug 9. PMID: 39122967.
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The transcript of today's episode can be found below 👇
Betsy Crouch (00:02.276)
Hi everyone, welcome back to At the Bench, the neonatal physician scientist podcast where we are incubating discoveries. I'm Dr. Betsy Crouch, co-hosting with Dr. Misty Good and Dr. David McCulley. Misty Good is doing other excellent work today. So David and I today have the honor of interviewing Dr. Wendy Chung. David, would you like to introduce Dr. Chung for us?
David (00:27.374)
Thanks, Betsy. It's great to be here with you. I'm David McCulley. I'm a neonatologist and a basic scientist here at the University of California in San Diego. And I am very excited to be able to introduce one of my very close collaborators and friends, Dr. Wendy Chung. I'm just going to say a few words to introduce Wendy, who I think will be a great person for us to interview for this program.
Wendy is the chief of pediatrics at Boston Children's Hospital. She is professor of pediatrics at Harvard Medical School. She was an undergrad and med student at Cornell and did her graduate work at Rockefeller and then did her residency and training in clinical genetics at Columbia University where she was for quite some time where I started working with her on genomics of diaphragmatic hernia.
And then just recently, Wendy has moved to Boston where she is now. She's a world leader in clinical genetics of many conditions that occur throughout life affecting both children and adults. But she has a special interest in pulmonary hypertension, breast cancer, obesity, diabetes, autism, and congenital malformations, including congenital heart disease and diaphragmatic hernia.
She's a national leader in ethical, legal, social implications of genomics. She's been running an NIH-funded research program for years to study these topics, and she collaborates widely. And I had to say, one of the funniest stories I have is I was asked to review a paper of which Wendy was a co-author, and I was trying to just make sure that I was okay with the editor saying that I collaborated closely with Wendy, and she said, don't worry, everybody collaborates with Wendy. So if we were using that as a limitation, We would never find somebody to review this paper. So I was very excited to be able to do that.
I love collaborating with Wendy. She is a fantastic person to work with. So I'm excited to talk with her here today. Wendy, would you mind just introducing yourself to the audience and saying a little bit about your work and kind of what compelled you to get interested in doing the genomics research you do?
Wendy Chung (02:35.965)
Sure. I can't tell you how excited I am to be here. I knew Betsy way back when and glad to be with back, bringing the band back together, so to speak. And David's been a long-time good friend and collaborator. So I'll give you the short version of how I got into this.
It's sort of been a lifelong passion and I think I was very fortunate to get bitten by the bug early on and sort of find my way. And I know not everyone does, but I got lucky. So as an undergraduate, I was a biochemistry major and I had the fortune of being able to spend summers at the National Institutes of Health and started working on phenylketonuria actually as an undergrad.
The biochemistry hopefully makes sense in terms of being able to understand that inborn error of metabolism. And at the NIH, even though I was in a basic science lab, had the real privilege to be able to meet patients with PKU in the clinical center there. And it all just clicked for me in terms of being able to see the patients, being able to literally take a blood sample from them back to the laboratory, doing the sequencing, trying to identify atypical forms of PKU and, for that condition, excuse me, for that treatable condition, trying to think about how to take that back to treatment to the bedside. And, with that really, helped me to understand what the value of having an MD and a PhD was in terms of being a physician scientist.
And I was fortunate that the year I started medical school was the year the human genome project was announced. And with that, you know, had been spending my summers doing sequencing the old fashioned way, know, radioactivity, Sanger sequencing, Dideoxy sequencing, reading those gels and having to pour perfect plates and, you know, like I said, everything the old fashioned way. But in doing that could really, I had a sort of idea of what one might do with the genome. I didn't know exactly, but I had these ideas based on how painful it was to do the way I was doing and could envision a way of being able to do it differently.
Some advice that I always give to students or to young people is, I didn't originate this, it originated really with Wayne Gretzky, but to think about where the puck is going to be, and to skate there. I'm not a hockey fan, by the way, but . . .
Betsy Crouch (05:04.528)
I was going to say, are you a hockey enthusiast? this a little known fact we're unearthing on this podcast today?
Wendy Chung (05:14.397)
But with this, really to think about what the future state is going to be. And it's hard to break in and sort of when there are 50 great scientists in an area to be 51 and to compete. On the other hand, when there are brand new fields emerging and the old guard don't know yet how to navigate that and can't quite figure it out, the new younger generation is nimble and can really be able to make a greater impact.
Wendy Chung (05:42.461)
So within that, I was part of that, very young crowd. But thinking about it, also did the calculation in terms of how long the predictions were to take the human genome and finish it up. And that was about 20 years. And again, remember I'm a first year MD-PhD student. I'm saying, you know, medical school, residency, fellowship. . . all of this is about 20 years. So, you know, we'll finish the human genome project and maybe I'll have some idea how we're going to actually use it.
Anyway, luckily Craig Venter entered the scene and the genome project finished earlier. I finished earlier than that and we still ended up on time, but it's proven to be just, I would call it a love affair in terms of trying to think creatively about what you can do with that information. Not just from a basic science point of view, but how you can actually use it clinically. And that for me is like putting both sides of my brain together in terms of being able to use that. So that's just been the story of my life and my career is thinking about that.
Again, just fortunate enough to see that early on and follow that passion. But within that process, there've been lots of twists and turns and we may get into some of them, but things, I thought some parts of it would go faster and some parts have been pretty slow, but other parts have certainly been speeding ahead. And my hope in the rest of my career is not just being able to find genes and diagnose conditions, but actually to treat them.
Betsy Crouch (07:07.534)
Yes, and of course, we're very excited to talk about that too. I do think that one of the goals of this podcast is to talk about overcoming challenges, especially as physicians scientists. Do you mind talking about what you alluded to as twists and turns? Do you mind talking about a challenge that you encountered during your physician scientist career? And yeah, please.
Wendy Chung (07:26.525)
Yeah, for sure. I think I was naive, to say the least. Up until the point that I submitted my first NIH R01 grant, I would say everything just worked. Got into great schools, did great things, got great grades, wrote great papers, got into great journals.
And then all of a sudden I was flying solo in terms of my first R01 grant and I just assumed, I mean, what did I know? I just assumed like you just get a grant, right? I mean, you write it, you do a good job and you know, they just give you money and you do good work and you go on from there.
Betsy Crouch (08:11.49)
I know, should we make a public service announcement? That's not the way it goes.
Wendy Chung (08:17.853)
And I had this very rude awakening, you know, in terms of getting triaged, not even scored, but triaged, you know, on the first submission and like, OMG, you know, that's the first time that's ever happened to me. And, you know, just really sort of sat there stunned, like, my goodness, did I really pick the right career for myself? Is this really what the big leagues is about? You know, this is not so fun.
Wendy Chung (08:43.261)
Anyway, I will say I think it took me longer than it should have to recover from that and to go forward and to pick myself up and dust myself off. But that was a real sort of shock to my system. Of course, now, you know, lots of times, thankfully, I don't get triaged very often, but lots of times that I don't get my grants and you just, thick skin, pick yourself up, dust yourself off, read your reviews, and try and figure out the study section.
What the dynamic was and what it was that they didn't understand that in terms of your message. Anyway, it's just, don't take it personally, I guess is my point for those of you who are young in terms of starting out. It's pretty insane that we've got exceptionally good people and still we only fund at the 10th percentile. And it's a bit of randomness in terms of who does get funded. And it's not when you don't get funded or don't even get scored. It's not that you're a bad scientist, not a bad person, not a bad thinker, not brilliant, not creative, not hardworking. It's just, it's a pretty insane system we have in the United States.
Betsy Crouch (09:51.62)
Yeah, mean, thank you. Thank you for saying that. for everybody who's now been not discussed, now they know that they're in good company with Dr. Wendy Chung, department chair at Boston Children's, amongst other preeminent scientists.
Wendy Chung (10:10.205)
Yep.
David (10:12.664)
Wendy, can I go back just to where you started? I think those programs for undergraduate students at the NIH can be really impactful. And I was just wondering, how did you hear about that? Because I mean, one of the things we're trying to do in this program is to present multiple different paths to doing physician-scientist-related work. And I have heard many people go through those undergraduate training programs at the NIH. And I just wondered, how did you hear about it? Were there mentors that you found? Anything else that seemed like it was particularly attractive to you? It sounded like you had a really good experience.
Wendy Chung (10:53.179)
Yeah, so now I'm going to go back even farther. So I actually have thought about this. What are the impactful things you can do for young people? And if you get people early and have an impact, you really can change their career, their trajectory exposure to things. So for those of you who are trying, when you think about your impact factor as a person, I will say that impacts earlier on, you get more return on your investment, I guess is what I would say.
A lot of the summer, not that everyone is going to follow in your footsteps, but there are people who will not have thought otherwise about it, who you really do make a big difference. So my story was a little bit, it dates back even farther. So when I was in high school, there was something at the time called the Westinghouse Science Talent Search. It's gone, changed names. It's been called Intel, it's now sponsored by Regeneron, but it was a national science talent search. And when I was in high school, I was fortunate enough to actually have won that and that paid for college for me. And as a finalist, they brought you to Washington, D.C. to get interviewed and tested essentially by a panel of scientists. That was the final part of the competition. And as part of that, that was the first time I was exposed to NIH. They had us tour NIH and introduce us to what NIH was. And I had never known what that was before that point.
Along that tour, met Seymour Kaufman, was eventually who I later said, by the way, you know, in the day, we didn't have email. So literally sent him a letter and said, I don't know if you remember me, but I was here for this Westinghouse Science Talent Search thing. I won it. I'm looking for a summer job. Would you have me in your lab for the summer? He said, of course. Anyway, I was cheap labor, so why not?
Wendy Chung (12:50.115)
Anyway, so from that, you know, continue the twist and the turns, but not just science, you biomedical science and being able to think about, like I said, this dual career of physician and scientist.
David (13:04.696)
Have you then referred, I mean, okay, so now we can maybe go into like a little bit of your own mentoring. So it sounds like you have found that trying to intersect with people earlier in their career can be more impactful. So have you referred other people to specific programs or what do you think you would recommend to people like me and Betsy who are now mentoring undergraduate students, med students, graduate students, and other later stage trainees like fellows.
Wendy Chung (13:39.227)
Yeah, I have to say I found it challenging as time has gone on to think about how to get just the right pairing in terms of this. And so I do different things. I think some probably more and less successful. So when I was younger, I literally would have each summer, you know, anywhere from five undergraduates or high school students. You know, I was younger and so they were.
It was sort of near peer mentoring type of thing, right? So they were, I was just a little bit ahead of them and they'd come in for the summer and that was always a lot of fun. Some of them to this day that came in as at that level are now MD PhDs themselves and now colleagues of mine, you know, doing various types of things. Not all of them, but some of them have, you know, gone through that path. For me,
Betsy Crouch (14:29.252)
This is when you were a young PI or at what stage?
Wendy Chung (14:32.111)
Well even before that. So I would say, you know, when I was a graduate student or a fellow, you know, I've always sort of had, like I said, sort of near peer mentors, or was a near peer mentor in terms of people like one or two rungs below me. The thing that's been challenging for me to be quite honest is as my science has matured and gotten more sophisticated, and I don't mean to say that in a obnoxious way, but it's just gotten much more technical.
Wendy Chung (15:00.515)
It's been harder to bring young people into the laboratory because just to get them up to speed where they could code or analyze data or do various things, it's just, you know, I couldn't, it's been very difficult for me to take sort of more junior people and bring them in. So we do have some opportunities. I'm in the rare disease space and so I frequently have over the summer family meetings where we bring families together with those rare conditions to learn from each other. I'll often do intensive research with the families at that point and then share back our learnings with them. So we've used that as a way to be able to expose individuals who don't have to be all that sophisticated about the science, but that can come and really, you know, are helping hands in terms of doing it, but they get to observe and they get to see what life in the day, or a day in the life of whatever it is is like, and be able to understand that. And that's been, for some, very impactful in terms of seeing what the impact we have on families is, and reciprocally the impact they have on us.
So anyway, we're still, I would say, trying to figure out what all the opportunities are. for some people, like I said, that... It's something they just didn't quite see how the pieces fit together when they actually see it in action and see the power it can have can really be transformative. Or they can realize it's not for them. And that's also good to be able to realize that's not the right hat and try on a different one.
David (16:36.302)
That's great. Thank you. Now, just trying to transition back to your career path and trying to think about the list of conditions that I kind of went through that you've studied. How did you begin on this path? So now at Columbia as a genetics trainee, how did you start to build your research interests? Which conditions stood out to you? Why? Were there certain clinical cases that stood out?
Wendy Chung (17:06.621)
Yeah. So David, you introduced the, you know, that I'm interested or have studied CDH or diaphragmatic hernia. So I still remember as an intern, a pediatric intern being in the NICU and taking care of babies with CDH. And I still very much remember being taught the dogma on rounds of looking at the chest x-ray, being able to see the intestinal contents up in the chest. I'll just never forget it exactly who told me and it making sense saying, and you see the respiratory insufficiency, it's clearly because there's just compression of the thoracic contents during development and completely made sense, right? Stands to reason you're squishing the lungs and they're not able to inflate and develop. surely that's why, and then having these babies in the NICU with us in some cases for weeks or months in terms of the respiratory insufficiency or pulmonary hypertension and saying, yeah, I remember what that chest x-ray looked like on day of life one. That's clearly what the cause is. At Columbia, had not to say that lots of other centers didn't, but we had surgeons that were really good at CDH surgery. We tended to get a lot of those. I saw a lot and it just kept striking me, this is a tough disease, a tough condition. We have a pretty high mortality and this is one of those things. The surgeons are good, but we don't seem to be able to always fix it. And I wonder why that is. So that was what started me in terms of that, really that question specifically, really making me scratch my head and try to figure that out. And as you know, it's taken 20 years for me to really be able to understand that better.
It's now becoming clearer to me, it's still not completely elucidated that all CDH is not created equal, it's not all the same. And intuitively, you guys know that as neonatologists, but it's hard for me to predict to this day just by looking at a chest X-ray, which baby is gonna fly and go home after repair and be okay, and which one is not gonna make it home from the NICU. And within that, that was the question that kept coming back to me as we then got into prenatal diagnosis and as I'd see these parents in our Center for Prenatal Pediatrics is what we called it at Columbia, but they'd be asking the obvious questions about, doc, what does the future look like? Should I be getting my hopes up or should I not?
And within all of this, just kept, like I said, I just kept going. It was an X-ray or it was an ultrasound or it was a fetal MRI, but I still wouldn't end up with the same question. I could not tell. We could do LHR measurements. We could try and estimate lung volumes. We could do all these fancy things, but you know, lots of times I was literally placing bets with myself in terms of what we'd see at the Center for Prenatal Pediatrics and what we'd see on the other side. There was a pretty good chance that I was gonna be wrong in many cases. So the genetics are now at a state where, you know, it's very complicated is the bottom line. It's not like there's one CDH gene, it's not even like there two or three, there are probably going to be over 100. But it is clear that some of the genes just have a bad prognosis. Unfortunately, that's what we're seeing. It's not like we're finding genes with good prognosis. Mostly we're seeing if we see an association, it's a specific gene with a bad prognosis. And now, thanks to work that you and Xin Sun and others have done, we can start to genetically dissect what are the effects in terms of diaphragm development, and not surprisingly, what are the effects on development of the lungs themselves. And so these are not simply just compression or mass effects. These are fundamental primary lung developmental disorders. We just don't usually do autopsies on those babies after they die. We oftentimes don't visually see on a chest X-ray that sort of granularity in terms of what the developing lungs really look like. And so I think we've been kidding ourselves in terms of just not really seeing the anatomical or microscopic detail.
And instead, now we're getting at the genetic detail and taking it from that point of view. But I think as we're able to do better lung imaging, better phenotyping in general, the genetics will be the foot in the door that pushes us in that direction. But I think we're going to suddenly realize there's a huge amount of heterogeneity in what we call CDH. It's definitely not one size fits all. And, you know, the next thing after that will be as well.
Diagnosis is nice, prognosis is nice, but let's do something about it, let's fix it. And that's not gonna be easy, but at least we'll start to understand the targets, the biology that we might want to be able to try and approach. So that's the first step.
Betsy Crouch (22:01.668)
Wendy, can we go back? Why do you think you aren't picking up resilience genes related to CDH?
Wendy Chung (22:08.101)
So in an interesting way, and maybe we'll get to this later, it's interesting what is out there that is just people doing their thing and people that are healthy and not coming to clinical attention and how would you ever know they're out there because who would have thought to look? So one of the interesting questions that I think about all the time is, who are we not seeing and why? And do they have these buffering, whatever you want to call them, resilience genes, buffering capacity, something else. And I'm convinced that if we actually had protocols to be able to visualize the anatomy of the body, essentially a high-resolution total brain MRI, or not brain, but total body MRI, to be able to look at things. There are a lot of people out there with things that
who knows, they're just living their lives, but they're the ones that we don't ascertain.
Betsy Crouch (23:05.742)
Yeah, but I mean, for example, we have a fetal treatment center at UCSF where we do catch some of these, you know, questionable CDHs versus an eventration. And so I think there's the possibility that we could have some of those cases, but are those families less likely to participate in sequencing? Is that the issue?
Wendy Chung (23:40.583)
Well, no, so to your point, anyway, I'll give you another funny story. We’ve had families over time that have been familial cases. We don't have very many of them, but we had one for a particular GATA transcription factor. And the way it looks like the variant was segregating, it looked like it was being inherited from an unaffected father and unaffected grandfather. And I thought this was, it's been a while now since we discovered this, but as I was looking at it, I said to myself, but that doesn't make sense. Dad is fine. How could you miss a CDH? Dad is fine. Grandpa's fine. The other family member that was affected died as a newborn. This little baby got picked up and fixed and that's why he was fine. But you know, you can't miss this was what I was saying. And as I was looking at the data, I'm scratching my head saying, well, maybe this isn't the answer. What could the answer be? So I'm scratching my head as I've got my kids at Disney World and I'm sitting in the line of Pirates of the Caribbean, one of those interminable lines. And as I'm sitting there thinking to myself, I'm like, how do I know that dad doesn't have a CDH? Did I actually look? And so it's at that point that I call up and I'm like, we've got a look. And so that was the first time we actually looked in him and we did an MRI and sure enough, he's got a very small hernia. He was asymptomatic and it wasn't so large that he ended up with herniation. And so he's been sitting there a long time with a minor defect, his father the same thing, they look almost exactly the same.
Wendy Chung (25:32.821)
That's what I meant by unless you image there may be all sorts of stuff sitting there that's subclinical, whether it's eventration, a small hernia, something else. And unless you look, who would know? So I think there, and I think just to be even further, I think there are certain organs that are more sensitive to anatomical differences, right? So the heart, like not as robust, even small things can cause big problems.
Wendy Chung (26:02.685)
But on the other hand, other organs that probably go through lots of variation, but you you'd never know because it's not that big a deal.
Betsy Crouch (26:11.022)
Yeah, Wendy, maybe you would remember the name of this professor. But when I was going through the neurology curriculum as a medical student at Columbia, there was this story about this person who used to be a department chair at Columbia who had never had any brain imaging and finally fell in the 70s and had some sort of brain imaging and had a huge like porencephalic cyst. And so this person had become a distinguished professor at Columbia and was missing a large portion of his cortex. And it must have happened early enough that his brain was able to rewire. So I think it gets to your point. But the heart, I agree, is very difficult. I guess one more question just about gene penetrance and dosing and modifier genes is just to think a little bit about the gender question or XX and XY. I think it is an important part of all of our grant applications these days to consider XX and XY effects, and so how do you broadly think about genetic variants on an XX or XY background?
Wendy Chung (27:18.107)
Yeah, so that's spending a whole hour doing this. So it is interesting because one of the conditions that we study is autism. And autism is one of those things that's quite gender dimorphic, four to one, approximately in terms of XX or XY to XX. And there's another condition I also study, pulmonary hypertension, where it's almost flipped the other way, where XX is much more susceptible.
Wendy Chung (27:47.581)
And then things like CDH, which are closer, a little bit more skewing XY, but still some skewing, some real skewing and even differences that we see in families. So the bottom line is, I don't know, I wish I had the answer, but we wave our arms in lots of ways in terms of hormones or... societal differences in diagnosis and who comes to clinical attention and, you know, all sorts of different things that we talk about. But the honest answer is I don't really know. And what it is that buffers, you know, what one gender versus another to certain things, frankly, I just don't know. I don't think it's just genes on the X and the Y chromosome, just for simplicity. It's more complicated than that.
Betsy Crouch (28:35.696)
Well, to be continued.
David (28:39.18)
Wendy, obviously I am similarly intrigued about CDH. And I think it was the heterogeneity in the patients that really caught my attention because I remember looking at similar chest X-rays and maybe even the opposite scenario where we had one chest X-ray where we would have predicted that the phenotype was going to be pretty mild. It ended up being lethal. And the opposite happened where we thought one baby was very likely not to be able to survive and actually did very well. And it just seemed like all of our prenatal predictions were not very good and that there had to be something more to it, including intrinsic defects in lung development that were based in some genetic cause that resulted in abnormal lung development or better lung development in other cases. But I just wondered in thinking about applying genomics approaches to babies with conditions like CDH or congenital heart disease or other things.
Is your main motivation to better understand the underlying pathogenesis of the disease and better subclassify the patients? Or is it thinking more strategically about like, should these patients be treated in different ways because they are in fact different from each other? Are those things in the same line of thinking or how do you think about that kind of thing?
Wendy Chung (30:00.413)
So a couple things. In the current era of genetics and genomics, without tooting our own horns, I do think it is the most rigorous, unbiased discipline there is in terms of truly understanding biology. So what I mean by that is now that we have the ability to do things genome-wide, we get criticized that we don't have hypotheses going into them.
I actually think it's just the opposite, that we're much more rigorous because we're not biased as we go in with preconceived notions. And that's basically what I think the hypotheses are. So we just follow the data. We see we're going to do this in an equitable way in terms of the genes, and we're going to follow the data and follow the science, and it will point to us what the biology is, and then we can go deep in understanding that biology. But that way we don't get diverted and go in the wrong direction.
Fundamentally, genetics to me is a powerful tool to in an unbiased rigorous way that is incredibly reproducible, find the truth with a capital T in terms of the underlying biology of whatever the condition is. And you can fill in the X for what that condition is, but it has consistently delivered in terms of that. So that's the first thing is being able to do that. And then you can go deep in the biology to understand mechanism, to think about how you want to associate clinical phenotypes, how to think about prognosis, how you think about therapeutics, you can build upon each of those depending on what your ultimate goal is. At various times I've done all of the above in terms of thinking about that. But fundamentally it has to start with discovery. I do hope we're getting to the point where, you know, we're not quite wrapping up discovery, but we've done a lot of discovery and now it is time for the field to move beyond just discovery. So, as I said, with that, it isimportant to think about what can you do with the information now that you have those pillars, those sort of that foundation to build upon.
Betsy Crouch (31:58.64)
Should we talk about discovery for a moment though? Specifically newborn screening in the context of our patients?
Wendy Chung (32:04.667)
Yeah. Yeah. So I'll take you back to what I started with before. So you'll recall that the first bug I got bitten by was about PKU. So without showing my age, that was a long time ago. And so it's taken a long time to get to this point, about 35 years, actually. So the next time that I sort of had this awakening was I had been working with investigators on spinal muscular atrophy. And without going into a lot of detail, I'll say I was tremendously influenced by a single patient. For me, it always starts with a patient and ends with a patient. And one individual patient in her family had a big impression on me and did a lot in terms of influencing my career, which included understanding the natural history of spinal muscular atrophy and with a lot of the partnership with her family and many others. We got to the point where we had the potential for an ASO, an antisense oligonucleotide, to be able to start treating SMA. On the other hand, I knew enough about the natural history and the degenerative nature of that condition that I was quite concerned that even with good therapy, if we didn't start the therapy early enough, the motor neurons would be dead and gone and we wouldn't be able to have the impact, even if the therapy theoretically was doing what it should be doing. If we just didn't get the timing right, we wouldn't actually see the impact. So as I knew that the trials would be coming, because I was sort of deep in the fields and I knew what was going on, I said to myself, how are we going to identify babies at the right time for treatment?
For this recessive condition, people would have said, well, you wait till they're sick and they come in. Well, that's like even for a type one baby, that's about six months of age on average. And so that's too late. So then we'd say, well, if a family had another child with SMA, they might get prenatal diagnosis and you'd find out about a younger sibling. And while that's true, that's not exactly the way you want to find out about someone having SMA, although you would know about it then very early on.
Wendy Chung (34:16.454)
And so I said, well, I think this is a pretty common condition, one in 10,000 births. Why don't we just brute force it? Why don't we start screening babies at birth? There's one particular mutation. I can get the cost of that assay very, very low. Why don't we offer, now that we've got a clinical trial coming, why don't we offer newborn screening and a consented research study? And it's not just diagnose and then wave goodbye adios. We can really offer, we can't guarantee it'll work, but we can offer now a clinical trial. And you can also decide not to do it, but on average, you know, we're going to expecting that you're going to with type one that your baby won't live to be one or two years old, you know, no longer than that. So that was what started for me. The first newborn screening pilot that I did in collaboration with the New York State Department of Health.
Wendy Chung (35:07.345)
That was truly, to me, without tooting our horns, truly remarkable in the sense that within a relatively short period of time, three years basically, we went from a pilot newborn screening study to FDA approval for that ASO. That then fed back because once we had a successful pilot for screening and an FDA approved treatment, we then could get that approved by the recommended universal screening panel. So we went again within three years to national uptake in terms of newborn screening for SMA. That started powering then the gene therapy trials for a one and done therapy. ASOs you have to repeat every three months. Gene therapy is one and done. So that was number two. And then number three FDA approval was for a third medication. And so within a brief period of time went from the most common genetic cause of death for children, less than two years of age, to transformative treatment, diagnosis and treatment in terms of being able to really change the future for that condition.
Within that, the next question came for me. We did a second pilot study for Duchenne muscular dystrophy. That was also successful, although each one of these incredibly resource intensive to do each pilot study. And by that time I was getting older and more tired and said, we have to think about a way of not doing this one by one, but how do we do this really for a platform?
Wendy Chung (36:51.405)
And that's, you know, one of the things I like doing is thinking about scale and thinking about platforms. And DNA sequencing is obviously a platform that can get hundreds of genetic conditions. And so the Guardian study, which I'm now running called Genomic Uniform Screening Against Rare Diseases in All Newborns, is aimed at health equity fundamentally. It's trying to make sure that we leave no baby behind.
Just a single platform through a public health system that gives us infinite flexibility so that as new treatments are developed, we can, because we do whole genome sequencing from that dried blood spot, simply open the channels of information based on what's treatable at the time that baby's born. And so today we may open 400 conditions.In six months when there are new approvals for new conditions. It's 401, 402, 403, but you just have infinite flexibility to keep up so that it's that time that sort of time for implementation is now measured. I would like it measured in weeks to months, not years to decades as we go forward. And so we're trying to really think forward in terms of that investment and how to get the maximal return on investment from those really intensive studies and all the contributions by the families.
Betsy Crouch (38:15.61)
That's so inspiring. And thank you for walking us through. You talked about being tired in terms of thinking, really in a visionary way about how to get the maximum impact out of the research dollars on the research efforts. But I would say that that's wisdom. So thank you for sharing that with us.
David (38:42.646)
I was just curious to ask a little bit about just how you have kept building in this way, because I know you're doing a lot of this work through the NIH and through these national collaborations. And I was just wondering, how did you get connected with that kind of work? And what is the work that you're doing now? Just thinking about that, like how you've used your genomics research and focus to really advocate for child health very broadly.
Wendy Chung (39:08.357)
Yeah. So I'll say this is perhaps the disappointing part. I'm optimistic in general. You know, I don't want to say I'm a Debbie Downer, but it is children's health and research for children is hard to advocate for. You know, our babies don't vote. It is, you know, I think they get neglected in many cases for reasons that to be totally honest,
Again, I think about very strategically return on investment and return on investment for a child is so much greater than no offense, but return on investment for a whatever, a retired adult or someone my age and older. So it's disappointing to me and there's so many determinants of health that start in children.
Wendy Chung (40:07.625)
And so I do really think about investing in our future. And so it's always disappointing to me that we can't think of the vision in terms of how to invest in the future and the health of the next generation. And I understand a little bit in terms of the forces and who's able to advocate with their congressperson or their senator or their president. I understand more as I got older how life really works, but I'd still say it's disappointing. And within that though, I guess the other thing I've learned is that patients and families as partners are very strong advocates. Putting together the combination of the scientists, the physicians with their voices in terms of helping pointing them in the right direction and having them push, you know, for really their families, their children.
To me, that is an important combination. And I'm not trying to be manipulative, but I do think it's important that they understand how to make sure their voices are heard.
David (41:15.97)
Yeah, I know, I think it's very compelling and then also as very motivating as an investigator and a clinician to be able to have the inspiration come from your patients and your families. And I think you're exactly right. That partnership is so motivating. Just thinking about the families that I've gotten to work with that have a baby with CDH and then connecting them with you to do genetic studies through the DHREAMS study. And just thinking about like how my work in the lab is directly related to my interaction with them and taking care of their baby. I don't know, I can't think of anything more compelling and motivating that makes me want to try to figure out what's going on. So I think that's a really good motivation and something that's in front of us all the time as clinicians that we, think, can connect with more to be even more motivated to keep advocating, because I think that's the thing. It's very easy to become frustrated and feel like people don't advocate enough or seem to invest enough in children's health. I there are so many compelling stories that we can, I think, be motivated by to help us keep making progress.
Betsy Crouch (42:32.28)
It's a story about why all of us are here, right? Wendy, you alluded to a couple of very poignant patient interactions. I have one that inspired me to really work on germinal matrix hemorrhage. I think it's the flip side for the how things really work spiel is that there are financial considerations and other demographic considerations, but there's also the consideration that a good story goes a long way.
I'm quite, I think that's something that I'll really take home from this is that, you know, I'm starting to work with families too in more or less direct ways. But we have a current study that we're working with a really excellent medical student who interviewed families who participated in research broadly in the NICU and asked what were their motivating factors that won't made them want to participate in research or discourage them with also an eye on equity, right? Like what are the things that we can do to include, to be the most inclusive we can in our research? And I found that talking with that medical student and her findings, and this is in collaboration with Mercedes Paredes, who's a really great developmental neurologist, I found that that can be often like one of the easiest parts of my day because it just speaks to this part of me that isn't a little bit my brain but it's like my brain and soul together that feels very natural I think to work on those causes so anyway there's my tangent. It's not only important to include our patients in our research but it's actually more effective when we work with our families to do our research in many ways.
Wendy Chung (44:22.545)
Yeah. I mean, I should have said to your point, for instance, the Guardian study was designed by families. So, right, the families that were part of the SMA newborn screening, when I came to them with the problem of like, I can't do this one by one, like, how do we put it together? This is the problem I'm trying to solve. What would you do? And that was the beauty of actually flipping it and saying, this is the study you designed essentially.
Betsy Crouch (44:29.474)
Yeah, what a nice story.
Wendy Chung (44:51.333)
I'll facilitate it. I mean, I'll get the work done because I know how to do that. But this is basically your study. That's been, I will say, the uptake rate for that study has been about 74%, which I think is about right. It's not 100%. It shouldn't be 100%. But it also was not 8%, which is what previous studies that had been similar to that were. And I think it's because it was the study designed by families to be what they wanted. Not by me with what I wanted, but what they wanted and what they needed.
Betsy Crouch (45:26.372)
Congratulations, what a nice example of doing that work well.
David (45:33.39)
Well, Wendy, I know you're busy and I really appreciate you taking time to talk with us today. We usually finish the show just with a segment about something that demonstrates our humanity, which I think you've already done. But just talking about things that we do outside of work or with our lab groups. And I just wondered, is there anything you do outside of work that you thought the audience would be interested to know about you? Just something that, you know, shows how your brain works and like what helps you keep going.
Wendy Chung (46:07.325)
So people probably won't be surprised after they hear this. I have two sons. And so we like to try and think of family activities to do. And one of them that we found that we like doing and actually do in various different places when we're traveling or going on scavenger hunts. So this gets, I have to say, this is not creative on our part, but there are folks that actually make scavenger hunts. And so puzzle in terms of, you know, going on a hunt around New York City or going around the Met or going around something and trying to find all the different puzzle pieces. So we always like doing it as a family. And as we're doing it, I realize that there are things that my sons are much better at figuring out than I am. And I'm really thrilled that I have them on my team as we're doing this. Ss we do it, we're probably a little competitive. we like, you know, trying to see if we can do it faster than the other teams that are doing it. You there are other families or other groups that are doing it. But we love doing it as a, you know, as a team sport, as a family to be able to, you know, see what we can do. Sometimes we try and up each other and sometimes we realize that, like I said, my sons are getting to be smarter than I am. So.
David (47:20.664)
Just out of curiosity, how old were they when you started doing this kind of thing?
Wendy Chung (47:24.903)
I don't know. think probably my younger one was maybe seven and fourteen, something like that.
David (47:29.315)
Yeah. That's about the age my son was when we moved to San Diego, and that's how we would get him out on hikes. There were these little treasures that were sort of buried on these hikes that we would go on in San Diego. So we had the same kind of thing. But that's great that you've used it as a good way of seeing an interesting place. The Met is already interesting enough, but you can have these little adventures inside something that's already cool. That's awesome.
Betsy Crouch (47:54.448)
Can you Google this? Can you Google scavenger hunt for and pick a place that you're going? Thank you. is very, this is, yeah, this is a great tip for life tips from Wendy Chung.
David (47:57.356)
Yes, that's a great suggestion.
David (48:05.27)
Thank you so much, Wendy. It was so fantastic to talk with you. I love hearing about your story and just getting to talk with you this way. So I really appreciate you taking the time.
Wendy Chung (48:17.745)
No, thank you for doing this. I actually found podcasts to be a great thing. I listen to them as I'm walking to work. hopefully I'll get to listen to this one too.
Betsy Crouch (48:27.118)
Yeah, please do. Can you give us that tip too? Are there certain podcasts that our listeners should know about?
David (48:31.778)
Yeah, what do you listen to? What other podcast do you listen to?
Wendy Chung (48:32.925)
Peter Atiyah is one that I like listening to.
Betsy Crouch (48:42.64)
I don't know what is that one about? Should I know?
Wendy Chung (48:44.573)
I don't know, he does, I've done one with him, but he does a lot more famous people than me usually, so, but various different biomedical things.
Betsy Crouch (48:52.624)
Okay, great. Thank you. Yeah. From the Incubator podcast, they have a journal club that's quite good and covers the recent journal articles and it's kind of like the Cliff's Notes versions of the things that I should be reading. I wish there was that type of thing for everything that I work on, but Ben and Daphna do a good job. Well, in the interest of time, we will wrap up, but thank you all to our listeners for engaging with us this year. It was our first year of the Incubator podcast at the bench segment and we couldn't have ended on a more distinguished guest who also showed us a lot of your humanity and what really motivates you so thank you so much it was an honor and we'll catch you all soon.
Wendy Chung (49:39.389)
Happy holidays.
David (49:39.726)
Thank you.