#345 - 🔬Genetics and Neonatal Lung Disease: A Conversation with Dr. Jennifer Wambach

Hello Friends 👋

In this episode of At-the-Bench, hosts David McCulley and Misty Good interview Dr. Jennifer Wambach, a neonatologist and researcher specializing in rare neonatal lung diseases. Dr. Wambach shares her journey into neonatology, her research on genetic lung diseases, and the importance of mentorship in developing future physician-scientists. The conversation also covers the Undiagnosed Diseases Network, current research on genetic lung diseases including ABCA3 deficiency, and the challenges faced in rare disease research. Dr. Wambach emphasizes the need for resilience and adaptability in scientific careers, offering valuable advice for early-career investigators.

Link to episode on youtube: https://youtu.be/XSmNnx8HA78

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Short Bio: Jennifer Wambach, MD, MS, is an Associate Professor of Pediatrics at Washington University School of Medicine (WUSM). Dr. Wambach is the co-program director of the neonatal perinatal medicine fellowship program at WUSM/St. Louis Children’s Hospital. Her research goals are to understand the disease mechanisms of rare neonatal and pediatric developmental lung disorders, to identify pharmacologic strategies for treatment of these disorders that are often fatal without lung transplant, and to use genomic and transcriptomic technologies to identify the genetic etiology of birth defects and rare phenotypes among infants and children

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Featured manuscripts from Dr. Jennifer Wambach

Nevel RJ, Brennan SK, Wambach JA. Genetic Disorders of Surfactant Metabolism. Neoreviews. 2025 May 1;26(5):e328-e338. doi: 10.1542/neo.26-5-014. PMID: 40306683.

Voss LA, Nevel RJ, Wambach JA, Nogee LM, Deterding RR, Casey AM, O'Connor MG, Craven DI, Taylor JB, Deutsch GH, Tam-Williams JB, Steffes LC, Brennan SK, Santiago MT, Sadreameli SC, Heras AF, Powers MR, Popova AP, Bansal M, Hamvas A, Gower WA, Urrego F, Young LR; ChILD Registry Collaborative. Genetic Testing Utilization in the U.S. Registry for Childhood Interstitial and Diffuse Lung Diseases. Pediatr Pulmonol. 2025 Apr;60(4):e71073. doi: 10.1002/ppul.71073. PMID: 40167520; PMCID: PMC11960725.

Wambach JA, Nogee LM, Spielberg DR, Cole FS, Roberts DM, Murphy S, Garcia CK. Interstitial Lung Disease and Lung Cancer Associated with a Monoallelic Novel Variant in SFTPB. Am J Respir Crit Care Med. 2025 Jun;211(6):1085-1088. doi: 10.1164/rccm.202412-2411RL. PMID: 39970392; PMCID: PMC12175957.

Sun YL, Hennessey EE, Heins H, Yang P, Villacorta-Martin C, Kwan J, Gopalan K, James M, Emili A, Cole FS, Wambach JA, Kotton DN. Human pluripotent stem cell modeling of alveolar type 2 cell dysfunction caused by ABCA3 mutations. J Clin Invest. 2024 Jan 16;134(2):e164274. doi: 10.1172/JCI164274. PMID: 38226623; PMCID: PMC10786693.

Wambach JA, Wegner DJ, Kitzmiller J, White FV, Heins HB, Yang P, Paul AJ, Granadillo JL, Eghtesady P, Kuklinski C, Turner T, Fairman K, Stone K, Wilson T, Breman A, Smith J, Schroeder MC, Neidich JA, Whitsett JA, Cole FS. Homozygous, Intragenic Tandem Duplication of SFTPB Causes Neonatal Respiratory Failure. Am J Respir Cell Mol Biol. 2024 Jan;70(1):78-80. doi: 10.1165/rcmb.2023-0156LE. PMID: 38156804; PMCID: PMC10768837.

Xu KK, Wegner DJ, Geurts LC, Heins HB, Yang P, Hamvas A, Eghtesady P, Sweet SC, Sessions Cole F, Wambach JA. Biologic characterization of ABCA3 variants in lung tissue from infants and children with ABCA3 deficiency. Pediatr Pulmonol. 2022 May;57(5):1325-1330. doi: 10.1002/ppul.25862. Epub 2022 Mar 17. PMID: 35170262; PMCID: PMC9148430.

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The transcript of today's episode can be found below 👇

David McCulley (00:01.816)

Hello and welcome back to At-the-Bench, the Incubator podcast focusing on neonatology physician scientists. My name is David McCulley. I'm a neonatologist and basic developmental biologist here at the University of California in San Diego. And I again, am very honored to be able to co-host this program with Misty Good. Misty, do you want to introduce yourself and our guest for today?

Misty (00:28.867)

Sure. Hi David and hi Dr. Jennifer Wambach. I'm Misty Good and I'm a neonatologist, scientist, and division chief of neonatology at UNC Chapel Hill. So honored to be co-hosting today and interviewing our very, very special guest who I've had the honor of working with for several years previously, Dr. Jennifer Wambach. Jen, would you like to introduce yourself?

Jennifer Wambach (00:55.105)

Hi, I'm Jen Wambach. Thank you for the invitation to chat today, Misty and David. I appreciate that. I am an associate professor of pediatrics and neonatologist at Washington University in St. Louis. And I do my clinical time at St. Louis Children's Hospital. I'm also the co-program director for our fellowship program. And thanks for the invitation today.

David McCulley (01:20.578)

Awesome. It's really an honor to have you here. You are a perfect example of a successful neonatologist physician scientist. And it's great to be able to talk with you about how you got your career started and what's been really interesting for you to study. I know you as a neonatologist who studies genetic mechanisms of newborn lung disease.

And I wondered if you could just give kind of a general overview of your research program, what you're focusing on now, and then we'll get into what motivated you to pursue that line of research.

Jennifer Wambach (01:59.491)

Sure, so my lab has really two main goals. So the first, as you described, we focus on rare neonatal lung diseases. St. Louis Children's Hospital is one of the few hospitals in the country that can offer infant lung transplant. We do take care of a number of these babies clinically, but I became very interested in these diseases because they usually have a genetic origin and I had a strong interest in genetics coming into neonatology fellowship.

And I also found them particularly interesting because they were usually not diagnosed before birth, unless there was a family history. These are typically term babies who for every intent and purpose should be healthy, but have severe breathing problems at birth. And unfortunately, we don't have a lot of treatments for these babies right now. So for those who have progressive respiratory failure, it's really lung transplant as the definitive treatment option. And so I'm very interested in trying to model these diseases after the success in cystic fibrosis. The specific gene I study, ABCA3, is very similar to CFTR. And so we're trying to take the lessons learned from cystic fibrosis and apply those to rare lung diseases, including ABCA3 deficiency.

And then the second focus of our lab is to use exome, genome, transcriptome genomic technologies to try to find the etiology of rare diseases in infants and children. And I have been lucky in my career to transition to faculty as many of these technologies were really becoming available and much less expensive. And so it's been a very interesting journey that I've taken with a number of families. Each baby or child has their own story in terms of how we navigate that process. We're very fortunate here to be part of the Undiagnosed Diseases Network (UDN), which is funded by the National Institutes of Health. There are 12 clinical sites, of which WashU is one of the clinical sites. We also have a Model Organism Screening Center facility which is part of the UDN. We have funding not only from the NIH, but also from the Department of Pediatrics and the School of Medicine to continue that work. So it's not necessarily a journey I would have predicted when I was a fellow, but it's been a lot of fun.

Misty (04:22.747)

I was going to ask you specifically about that if you could just tell our listeners about your journey and when you really started to get excited about science and was it a particular patient or mentor or where in your career path did you get bit by the scientific bug?

Jennifer Wambach (04:40.953)

Yeah, you know, I think I did some bench research in college and enjoyed that. At that point, I was contemplating whether I wanted to pursue graduate school, the PhD route, versus go into medicine. I spent a summer studying a flowering weed species in Virginia. And we collected leaves and did genotyping. That was my first, real hands-on exposure to genetics. And I really enjoyed that aspect, but I missed the people part of it. So at that point I decided that I felt drawn to the clinical aspects of science, the medical aspects of science. And so I decided to pursue an MD degree. And, you know, to be honest, I was not that aware of MD-PhD programs at the time and seven years seemed like a lifetime when I was 22. So I went to medical school and finished residency. And then when I was looking for fellowship positions, I was still interested in research. I wanted to be at a place where there were a lot of research opportunities available. And so that's what I found at Wash U in St. Louis. I've been here ever since. And then during fellowship, I found wonderful mentors who were interested in genetics and combined that with neonatology. And I think that's when I really saw those two things coming together.

David McCulley (06:05.708)

That's really exciting. It's really helpful just to hear what motivated you and how you established your path in the course that you've taken and just been so successful with. You mentioned just in your overview about how genetics was something that was really motivating or interesting for you. And it sounds like even as an undergrad, you had some experience doing genetics research. Can you explain how going from plant genetics was stimulating to you and then how 

you thought you might be able to pursue a genetics research field maybe during fellowship?

Jennifer Wambach (06:43.041)

Yeah, you know, I think neonatology was particularly interesting to me because there is a lot of genetics involved in the care of critically ill infants. And so I think those two kind of naturally came together. You know, I briefly contemplated pursuing clinical genetics, but I really like the fast-paced environment of the NICU ICU care. I really enjoyed that. And so, you know, I think my first project in the lab was actually looking at gene code variants, DNA variants in the surfactant protein C gene in a cohort of infants. And so at that time, we were doing sequencing one gene at a time. And then over the course of my fellowship, that was really expanding. We went from one gene to five genes, and then we had a 1,500 gene panel, and then we went to exome and genome. I was very lucky to be doing my training and early work when that dramatic change in genetic testing was available. And there were so many applications to the NICU. And so I remember being able to access exome sequencing through a research basis and just thinking about all the families that we were going to help find a diagnosis. All the infants that, at that time, we really didn't have answers for why they were sick, many of whom had passed away. And doing a trio exome sequencing identified the cause of some of those birth defects or some of those severe, extreme phenotypes. And that was very rewarding. It was an interest in two different fields coming together, I think, at the same time for me.

David McCulley (08:30.478)

That's exciting. I wanted to say, I remember, and this must have happened probably near the end of your training, but I remember we were sending samples even from UCSF. So I was a fellow in neonatology at UCSF and WashU was just known as this place where people were doing really cutting-edge research investigating the genetic basis of complex lung disease, just like you talked about. I mean, you were, I think the leaders in the field were at WashU at the time. And it was exciting because we were so limited in the things, like you said, that we could offer families in terms of trying to figure out what the diagnosis might be. And it's been amazing over the last 15 years that technology has changed so quickly and we've been able to make so many more diagnoses for these families who have babies with complex diseases, especially newborn lung diseases like you study. So it's been very exciting. And it seems like even in addition to offering a potential answer to what the underlying condition actually is, you are now building toward the possibility of using the genetic diagnosis to derive new therapy. I'm sure we'll get into that, but that must have been one of the motivating ideas as well.

Jennifer Wambach (09:53.827)

Yeah, for sure. We have a lot of consultations with now virtual technology, they used to be via conference call, but now virtual, with families and neonatologists all over the country when they encounter these rare genetic lung diseases. And each neonatologist will maybe see these disorders just a handful of times in their career. But we can offer a potential therapy and walk the family through that process. I think that is a very important part of my job and I get to interact with neonatologists all over the country through that. Right now, the therapies are very limited, as you said, but we do have hope for gene therapy for some of these disorders. There are mouse models where we use gene therapy, meaning a collective scientific environment, to correct surfactant protein B deficiency. As I mentioned, we're very interested in identifying medications for ABCA3 deficiency and potentially gene therapy for ABCA3 deficiency. I think understanding the genetics, the biology is really critical so we can develop these therapies. But yeah, it's really exciting to think that hopefully by the end of my career we will have therapies for these previously fatal disorders.

Misty (11:17.671)

That's fantastic. As someone who used to work together with you and now I'm at UNC and you are at WashU, for us, it's a wonderful resource when we have a rare genetic lung disease or even a suspected lung disease that we can pick up the phone and chat with you about it. I was curious because we do have a lot of fellow listeners and they, I think, look at a lot of the people that we host and think “that can never be me” or that “I can never be an expert” in this field, but you have really shown the interest in the rare genetic lung diseases and have become the go-to person for all of us, a consultant for around the US and probably around the world. I'm curious if you could tell our listeners how that journey happened. I know you were funded with a K and you've been incredibly successful from a grant standpoint. Could you talk a little about your early collaborations and mentorship along the way and how you went from graduating fellowship to the expert that you are now?

Jennifer Wambach (12:45.075)

Well, that's very kind of you. I think I'm always learning and there's a lot more to learn for sure. I think one of the exciting things about being able to offer clinical exome, clinical genome sequencing as we're identifying even more rare diseases associated with lung disease and neonates, but also other phenotypes.

I'll be honest, when I first started in the lab, I was interested in the gut, the intestine. But my mentors were interested in the lung. And so I said, I like genetics, I could learn to love the lung and I do. And now, I've learned to love it along the way. But, really, really mentorship, I would say, is probably equally, if not more important than the actual organ system, you know, especially when you're a fellow.

And I had wonderful mentors, Sessions Cole and Aaron Hamvas were here at Wash U. as David mentioned. They are experts in the field of surfactant biology. Actually, the very first infant with surfactant protein B deficiency was identified in the St. Louis Children's Hospital, NICU. And it's actually a very cool story. Aaron Hamvas and Sessions Cole were attendings on service. Larry Nogee was a junior faculty and Robin Deterding, who is now a leader in pediatric pulmonology, was a medical student. It is amazing how one patient can influence so many careers. But yes, Sessions Cole, Aaron Hamvas were my mentors during fellowship. Larry Nogee is at Johns Hopkins, is the individual who's identified many of these disorders. He has served as a mentor for me as well. I got to know Larry going to conferences, presenting posters, and he would come up to my posters. We would have breakfast meetings with Drs. Cole and Hamvas. And I really got to know Larry in that capacity. And then, you know, one thing sort of led to another, and I got to know other pediatric pulmonologists who were really interested in these rare diseases beyond the neonatology community including Robin Deterding, I mentioned, at Colorado Children's, and Lisa Young, at Children's Hospital of Philadelphia, have also been mentors for me. We've never been at the same institution, but given their expertise and leadership, they've given me a lot of opportunities, and we've collaborated scientifically. It came with time, and focusing on a couple of projects. Getting those projects to the point where they could be a presentation, whether that was a poster or a platform presentation. Having people come up to you afterwards, ask you questions, you're trying to follow up on those contacts. And then, you know, I know people say you should say no a lot, but I think saying yes is also helpful. Trying to take advantage of those opportunities to interact with faculty, whether that is going to a conference, whether that's joining a webinar or joining an interest group. That is a really good way to make some of those connections. 

Misty (15:53.106)

Yeah, I think that's a great point. You've been so successful at being able to do that, and now as a fellowship director, you are mentoring the next generation to be able to do that and enable people to become neonatal physician scientist is incredibly important. I don't know if you want to talk about that at all.

Jennifer Wambach (16:20.193)

We have a large fellowship program and Sam Julian, my program co-director, and I are charged with helping them find their research mentors. It is an exciting time to be a part of their career and try to help guide them toward research that they may be excited about. Some people come in with a sense of being more open minded about the project they want to pursue and we try to help them identify mentors who will be really invested in them and help them develop a project of their own that they can pursue during fellowship has been really rewarding. We have had several fellows who have gone on to become physician scientists. That has been fun to watch their career development and be a small part of that process.

David McCulley (17:22.604)

Yeah, you have a fantastic program. It's been so successful, definitely a leader in terms of being able to help physician scientists get great mentorship and build the early part of their career. I was wondering, because you are the fellowship program director, if you could talk about this for a minute. I remember interviewing when I was looking at fellowship programs at UCSF and I got to meet with Ron Clyman, who is an expert in PDA, who gave me really good advice, which I keep passing on to people. He said that I should try to find a mentor who would teach me to ask really interesting scientific questions and that that might be a more impactful role for a mentor than even having a specific mentorship on the topic that you really want to study in the future.

His idea was just you shouldn't necessarily go looking for a lab or a mentor who's going to be doing the exact work that you want to do. You should try to find a mentor who has an eye for identifying interesting questions that will be motivating for other members of the lab to study. I don't know if that's something you seek out, but I thought it was great advice and I keep reflecting back on it and trying to think of how I can help incoming fellowship applicants or even medical students find great mentors.

Jennifer Wambach (19:03.875)

Yeah, I think that's great advice. I think each fellow is a little bit different in terms of the support they need for their fellowship project. Some fellows are comfortable with open-ended questions like that and find those questions and we can help support them with like a mentoring team if there's not a specific mentor doing that work. You know, I think others need a little bit more structure and so connecting them with someone who has a track record of training physician scientists or clinical fellows so they have some of that structure. Hopefully they can build on that whether it's a similar project along those lines or a small tangent. I think each person comes in with a different background and interests. Trying to individualize the fellowship project is something that we've really been trying to work on.

David McCulley (20:10.818)

Yeah, it's worked well. You're doing great.

Jennifer Wambach (20:13.709)

Thanks.

Misty (20:14.813)

Jen and I used to work on the fellowship together and she was always the one who could find the perfect mentors across all of WashU. We went and talked to them and aligned the expectations. It was just such a great experience working with you on that.

Jennifer Wambach (20:36.088)

Thanks.

David McCulley (20:36.256)

Okay, can you talk about that a little more? That's an interesting idea. WashU is such a great resource. I mean, there's such a wide range of research topics that are being investigated on that campus. Just because you were looking for potential mentors outside of neonatology or maybe even outside of pediatrics or maybe even outside the medical school. Can you talk about that a little bit? That is something we've tried to do here at UCSD as well. And I think there is always some trepidation about how are we going to have a neonatology trainee who's got service responsibilities and call time be a successful trainee in this research environment, which sounds outstanding, but it might be difficult in terms of how to structure it.

Jennifer Wambach (21:24.535)

Misty and I spent a lot of time buying people coffee and talking about their work. Each fellow is different in terms of what they're hoping for in a research project. And when there is a fellow who has interest in an area no one in our division or even department is working on. Certainly we've gone outside the department. It's a very collaborative environment here at WashU and I've sent many emails to people to ask if they would be willing to meet or have a quick zoom to talk about what our fellowship is like and how much time our fellows have for research. And I usually do those introductions. Sam and I usually do those first to get a sense of whether it would be a good fit for that faculty mentor. And then often that very first meeting of the fellow and the faculty mentor, Sam or I is on so that we can be there to answer any of those logistic questions. How many months of service do you have? How busy is the first year? What's a call? Can you work the next day? We can sort through those logistic questions that a faculty member outside of our division or department may not be familiar with. That has worked really well. I think one other tip that I have learned over the years is that it's very helpful to also have someone in those labs where that fellow can meet with that person daily, whether that is a lab manager, a postdoc, a staff scientist, someone who can serve as their point of contact. Often the mentors are quite busy, writing grants, in meetings, or on service. But having that person that they can go to pretty much every day has been important in their success, especially as they're building their skills and experience with techniques.

Misty (23:31.773)

I was going to ask because you touched on it, if you could talk a little bit more for our listeners about the Undiagnosed Diseases Network (UDN) and how that goes from the patient to the bench and back to the bedside because I think it's just such a unique opportunity to be able to see science translate to the patient. So, we're hoping you could talk about that more. 

Jennifer Wambach (23:58.989)

We became part of the UDN in 2018. We were very excited to be selected for phase three. Patricia Dickson is the chief of clinical genetics here at WashU in the Department of Pediatrics, and she's the PI. I am a co-investigator for the UDN site here at WashU. There are 12 clinical sites throughout the country and a centralized application system. So a family or an individual, we take both pediatric and adult patients to the UDN, will apply to the UDN through this portal. Then depending on the geographic location of their home residence, they will be referred to one of the UDN sites. Then we review the applications. All of the applications include a letter from a physician and we review the referral and medical records.

We really try to identify those individuals whom we think would most likely receive a diagnosis from whole genome sequencing who have an underlying genetic condition. To be honest, most of the families who come to us now through the UDN, their children or the adult has already undergone whole genome sequencing. We review some very complex cases and now we have the technologies to try to identify those monogenic causes of extreme phenotypes including birth defects. And so those are the individuals whom we are most successful in solving through the UDN. So if an individual is selected for the UDN, then they come on site and they have a clinical evaluation. About half of our referrals at WashU come from outside WashU and about half are actually internal.

Jennifer Wambach (25:54.037)

And so after the clinical evaluation, we review all the available studies, we review the whole genome results, that may include a clinical whole genome which is done at Baylor. And usually we do not find the answer with the clinical whole genome. And so then we proceed with research re-analysis. We have a wonderful team of bioinformaticians here, led by Dan Wagner and Alex Paul, who reanalyze whole genome data to try to identify a genetic etiology of that individual's rare symptoms or rare disease. And then it becomes very individualized at that point. In some cases, there is a candidate gene that is identified that maybe has been studied in a model organism and is associated with a similar phenotype. In other cases, there may not be much that is known about that gene. In that case we use resources like gene matcher, which is kind of like a matchmaking database where individuals can put in de-identified information about a gene, or about a phenotype, and then hopefully match with other investigators or clinicians who are interested in a similar gene. And so we've solved a number of cases that way. We also have the Model Organisms Screening Corps (MOSC) as part of the UDM. And so some candidate genes or variants will be nominated to the MOSC, as it is called.

They will review those genes or variants to study in the fruit fly, the worm, or in zebrafish. It's often a combination of those resources. We do do some in vitro studies in our lab. Those might involve cell culture, RNA sequencing, or newer technologies to solve some cases like long-read DNA sequencing or long-read RNA sequencing. There are interesting tools that are available on a research basis which are not available clinically and not covered by insurance which we are able to use for individuals in the UDN.

Misty (27:58.141)

Amazing.

David McCulley (27:59.04)

Yeah, can I ask you some more questions about that? Just because I think that might be something our audience maybe doesn't know as much about. You said you use a screening process. Does each site screen cases, or do you get sent cases based on your site's expertise, or how does that process work?

Jennifer Wambach (28:19.885)

We receive applicants based on geography. We cover a 6 or 7 state catchment area in Missouri and our surrounding states. So we review the applications in our region. There is not a specialization within the sites. I will say that for some of the unsolved cases we have meetings that involve all of the sites where you might discuss an unsolved case. And there are certain experts that may present. We use the resources available here at WashU, using all of our experts as part of their clinical visit. As an example, they will see an adult rheumatologist or adult infectious disease experts, it really just depends on their symptoms.

David McCulley (29:15.768)

And then same for the model organism core facility. Do each of the sites have a similar thing, or do they all have their own based on their expertise?

Jennifer Wambach (29:25.847)

Yeah, there are model organism screening cores at Wash U, at Baylor, and in Oregon. And so there's only three model organism screening core sites. And so they receive referrals from all of the Undiagnosed Disease Network (UDN) clinical sites and then based on homology and what's known about that ortholog in the individual worm, fish or fruit fly and as a group we decide which organism would be best to model.

Misty (29:59.036)

And do the Model Organism Screening Centers (MOSC), do they have different areas of expertise or how are they organized?

Jennifer Wambach (30:06.254)

It's really based on organism. Yeah, so you know which organism they think would be best to study that candidate gene.

David McCulley (30:13.832)

And the mechanism I suppose as well. Yeah, really interesting.

Jennifer Wambach (30:15.117)

We have a number of investigators on campus who we reach out to if, for example, there's a gene identified as a potential explanation for a particular phenotype or a participant’s phenotype. And there may be an investigator on campus who's already studying that gene. They may already have the tools to model that variant or they may have never identified a human with a condition related to that gene. Each participant has their own story but the Model Organism Screening Center is very helpful to have as a resource.

David McCulley (30:58.966)

It's so exciting just because it demonstrates like the power of doing genomics for one thing. The other is that having a multi-institutional collaboration which allows you to figure out diagnoses for rare and complex conditions. There are also potential treatments coming from these investigations as well. I clearly takes a very multidisciplinary research program to be able to do those things for very rare cases. Each one is very complicated, as you said. The phenotype is often difficult to really understand fully. And then to be able to understand the genetic basis of the disease is difficult to demonstrate as well. So doing this work in a very multi-institutional program is just so exciting, just inspirational for all of us who do this kind of work and are hoping to be able to provide answers for families and offer the hope for some treatment in the future. So it's very exciting.

Jennifer Wambach (31:57.337)

Yes, for sure. It's been a wonderful group to be a part of and we hope it continues in the future.

Misty (32:04.739)

Fantastic. I wanted to shift a little bit just to talk about your recent work and you know current active studies happening in your lab and research program. I saw you had written a paper on interstitial lung disease and lung cancer associated with with surfactant protein B. 

As neonatologists, certainly we don't see lung cancer per se. Can you talk a little bit about that and your current work and how it all comes together.

Jennifer Wambach (32:42.777)

So that paper was a rare form of a rare disease. So there were two infants who came to us for lung transplant evaluation who had the typical genetic testing, whether that's a panel or exome sequencing, but were only identified to have a single variant in the surfactant protein B gene. And for one infant, it was inherited and for the other, it arose de novo. The clinical labs were not necessarily calling this as pathogenic because surfactant protein B deficiency is an autosomal recessive condition and in this case there was only a single variant. We had these two cases, it was the exact same variant and obviously suspicious that maybe this was a different mechanism.

We, over time, Larry Nogge and I collaborated with some other individuals, David Spielberg in Houston, and gradually identified more individuals, especially for the family in which it was an inherited variant. And there were some adults with pulmonary fibrosis, some adults with lung cancer, some of whom had been sequenced, some of whom hadn't. But it seemed that this variant tracked with multiple different lung phenotypes.

And that's actually pretty similar to what we see with pathogenic variants in the surfactant protein C gene. It was just really the first time we had seen this for the surfactant protein B gene. And then Larry happened to be at a conference with Christine Garcia, who does a lot of work with adult pulmonary fibrosis. And they were talking and she had several pedigrees where they identified the same surfactant protein B variant.

in these extended pedigrees of adult interstitial lung disease and some had lung cancer. Putting all that together, we identified multiple individuals again for whom this was acting in a dominant fashion who had lung disease ranging from neonatal respiratory failure to childhood interstitial lung disease to adult pulmonary fibrosis to adult lung cancer.

Jennifer Wambach (34:53.933)

We published those pedigrees to make this information available for clinical labs. This will enable individuals who do carry this variant to receive a diagnosis. We actually had one case where they were about to do a lung biopsy because this was the only variant identified. And after some discussion with the clinicians and the pathologist, it was found that this was the diagnosis.

We like to think we saved that baby from a lung biopsy. It is exciting and again, a rare form of a rare disease, but I think it demonstrates the importance of studying rare diseases and how that may have applications to more common diseases like pulmonary fibrosis or lung cancer.

Misty (35:41.565)

That's fantastic. Awesome work!

Jennifer Wambach (35:48.506)

Yeah, so now we have to understand the biology behind it. So that's a project we're working on next. We do try to collect specimens from infants and children who have these rare conditions. And we are so thankful to the families who agree to participate in research studies and who help other individuals who affected by the same condition. We also have a collaboration with Daryl Cotton, who's at Boston University, who takes skin fibroblasts from infants and children with these rare lung diseases and developed iPSCs, induced pluripotent stem cells, and then induced alveolar type II cells to model these disorders, again, with the goal of identifying therapies.

David McCulley (36:31.948)

Yeah, that's very exciting. The next level of getting to individualized patient treatment based on the individual genotype and using cell-based biology to do this work is really exciting. You highlighted an important point which I think people who think about genetics are aware of, but I don't know that everybody still thinks about it that much yet, just that even though one gene might be implicated, what the actual variant is in that gene can have a dramatic effect on the function of the protein and the ultimate phenotype. You write about that idea, your publications demonstrate the importance of that, and your description of this surfactant protein B variant associated with cancer demonstrates that concept. It is just complicated. For many people who are thinking, okay, I have this disease. I know this gene is associated with this disease, but it really can vary widely how the phenotype is manifested because the actual mutation that that patient has is so different from the mutation that another patient has. Can you just give some general thoughts about that highlighting the complexity that's involved in thinking about how do we translate a patient's genotype to a phenotype to a therapy?

Jennifer Wambach (37:57.572)

Yeah, it's a great question. You know, for ABCA3, which is the gene that we study most in our lab, there's a pretty clear cut genotype-phenotype correlation. Like if you have biallelic loss of function variants, whether that's frame shift or nonsense, those infants all present with neonatal respiratory failure and sadly pass away in the first few months of life without lung transplantation.

But if you have a missense variant in trans with either a loss of function or another missense variant or a different type of gene variant, then it's much harder to figure out what the prognosis is. That's really when you have to go to the cell-based models to try to figure out how are these different variants causing disease. We've done that for some of the disease-associated ABCA3 variants.

We have cell systems where we can express these missense variants to see how they disrupt surfactant metabolism in the cell. We know that there some that interrupt trafficking of ABCA3 to the lamellar bodies. We know that there are some that traffic normally, but then they don't pump phospholipid.

And so it's really important to understand the individual mechanisms because I think that's how we're going to be able to identify therapies. And, I go back to the model of cystic fibrosis, where a lot of their therapies are based on the mechanism of the individual CFTR variants. I think for the babies who have biallelic loss of function variants, like those babies really are going to need some sort of gene therapy or CRISPR editing. For some of the individuals who have missense variants, there may be medications which could help restore trafficking or could help open up the transporter or improve transport. So, yes, it's what makes exciting, it's what makes science complicated, but also exciting. And when you see those correlations, or identify those associations, it is gratifying. Many times we are trying to put all the pieces of information together.

Misty (40:29.469)

It's so challenging studying the rarest of rare diseases. And I'm just wondering if you could talk a little bit about that or any challenges you faced as you've been building and sustaining your research career. 

Jennifer Wambach (40:54.775)

Yeah, you know, I think they are certainly rare disorders, but I think a number of them do have applications to more common diseases. You know, I talked about ABCA3 deficiency, which is autosomal recessive condition. You need both copies of the gene to be affected to have the disease. But we have found that if you have just a single variant in ABCA3, those babies are much more likely to have respiratory distress syndrome when they're born, even at term or late preterm. And many of them get better with some CPAP and maybe intubation and some surfactant. And eventually they do quite well. But I think it's been very interesting to find that, yes, these individual diseases are very rare, but they do have implications for common conditions. Resilience is important. Some discoveries in science come very fast and are very exciting, like the surfactant protein B (SPB) story I was telling you about with the association of that variant with the diversity of phenotypes. And then some of them take a lot longer to figure out. I received some good advice when I was a fellow, which is that a researcher should try to mimic being a farmer. A farmer has multiple crops going at once, right? So you're planting in the spring to harvest one crop in the fall and the other one you're going to harvest earlier, the next one later. But really it is good to have several projects going as much as you can so that those which are quick can be wrapped up relatively quickly, but those which are longer, can kind of be interspersed with ones that hopefully finish up earlier.

Misty (42:44.989)

I love that I will bring that to the lab this week, some advice I just got is to be like a farmer. That's why we have so many ongoing projects. Because you know, sometimes people in the lab only want one project. I think it is good to have a high risk and a low-risk project. We really want to, especially for fellows in a condensed timeframe, complete fellowship with a publication, you need a shorter-term or low-risk project also gets to see the light of day. Thatthe high-risk project, might continue longer, like a farmer's crops. 

David McCulley (43:29.13)

It is great advice. The thing that I wondered about was that I remember people telling me to focus. So that is where that idea where you really need to focus on one project, just make sure that project works. But that doesn't often work. Often there is something that seems to be something that will be easily overcome. But instead, it becomes a major barrier by the end.

There probably isn’t a single best way to give people advice about that. But I like the idea of just having diversity in their projects. I like what you said about approaching research as a farmer. Having the foresight that you have to have as a farmer and the ability to anticipate the unanticipatable. Like, what happens when the weather is terrible and there is a massive flood or something like that. How do you plan for those things that you can't foresee?

Jennifer Wambach (44:30.115)

Yes, I'm not sure I have an answer for that. There've been a number of challenges, you know, just in the 15 or so years of my career as being faculty. In terms of COVID and funding and all of those things out there. I’ve been lucky to have the support of my division, my department, the medical school to continue this work. 

David McCulley (44:59.64)

You’ve also demonstrated very successful collaborations with people outside your institution as well. I'm sure those have helped you keep making progress and have a diverse research repertoire. Those inter-institutional collaborations inspire me. I think they tend to be the source of the most interesting questions because people approach these ideas from slightly different perspectives, and you can learn from each other.

Jennifer Wambach (45:33.57)

I think that is one of the most fun parts of being a physician scientist is having those collaborations outside of your institution. Whether you see those collaborators once a year or twice a year, you know, it's always fun to connect over science and share interests and it's special to have those relationships. And I have enjoyed that part. I didn't consider that when I was a fellow, but it's been one of the more rewarding parts of my career.

Misty (46:04.633)

Speaking of fellows, as we kind of come to the end of this, I wonder if you could share the best piece of advice that you received or that you would like to share with our listeners, either fellows or early career investigators who are pursuing a physician scientist career. What would you tell them?

Jennifer Wambach (46:33.561)

I think you don't have to have it all figured out today. It’s great to have an open mind and give science a try. There are going to be setbacks and things that don't work out. That’s just par for the course and part of the process. Just keep asking questions. It's okay if you don't know all the answers. I think one of the most fun things about science is that the field does evolve quickly. I feel like I'm constantly learning new things. In some ways that is challenging because I never feel like I'm the expert on anything, but it's also what makes it stimulating and rewarding and exciting. Keep an open mind. Hang in there. If you have to pivot and work on a different project, it's going to be okay. Try to keep working hard and make sure you enjoy what you're doing because, ultimately it's your career and you have to be happy day to day.

Misty (47:40.571)

That's wonderful advice. Hearing you talk about that warms my heart and makes me miss working with you.

Jennifer Wambach (47:49.433)

Yes, for sure.

David McCulley (47:54.872)

Can I ask one more question? We usually try to end our shows with something that demonstrates our humanity as people who do this kind of work. We often ask what's something that you like to do for fun with your research group or maybe with your family? Is there anything in particular that is a hobby of yours or that you just like to do to clear your head?

Jennifer Wambach (48:23.169)

We were a big soccer family. I have three boys. I just dropped off my oldest for college, which I am happy that he is going to Wash U because I've seen him, I think, four times in the last eight days. It has made the transition easier for me. He plays soccer and then I have a 13 year old and 11 year old who plays soccer. We are season ticket members for the St. Louis City SC. I'm excited to have our own soccer team in St. Louis. And one of the things that I enjoy doing is bringing my laptop to soccer practice and soccer games. I think some of the other parents wonder why I'm like working all the time, but I really appreciate the flexibility of being able to, 

take part in those events and I can type out some work that does not take quite as much concentration. Sometimes I get good ideas out there too. So I'm the mom with the laptop at the soccer practice or the soccer games, but like I said, I've appreciated the flexibility.

David McCulley (49:44.588)

Yeah, you never know when that inspiration is going to strike. So you have to be ready. I have a notepad that I bring so that I can write things down. It's like, I'm at an event and constantly churning and something will click. 

That's a great, that's great. We, we are very thankful in San Diego we have the San Diego FC, which is a new team this year. And so my family and I went to go see them play the Portland Timbers over the weekend, which was fun. Soccer has been a big part of my life as well. So that's awesome to hear. Thank you.

Misty (50:19.805)

Great to talk about work life integration, right? Like you're doing it every day. So thank you so much, Jen, for being on our podcast. We really appreciate hearing about your career journey and how you've become a leader in this field. We are so grateful to have you share your words of inspiration with us and our listeners. And thank you so much.

Jennifer Wambach (50:48.983)

Thank you. Thank you for the invitation and always good to see you Misty and David and appreciate the invite.

David McCulley (50:55.992)

Yeah, thank you so much, Jen. Thanks also to our audience. We are so lucky to be able to host this program. And hopefully this is another inspiring show for you to listen to. And we'll be back here soon with another interview from At the Bench. Thank you all so much for tuning in. And we'll talk to you again soon. Have a good day.

Misty (51:15.985)

Take care.