#380 - 🔬 Can Stem Cell Therapy Transform Outcomes for Babies with Lung Disease?

Hello friends 👋

In this episode of At the Bench, Misty Good and David McCulley interview Dr. Bernard Thébaud, a neonatologist and leader in lung and pulmonary vascular developmental biology and regenerative medicine. The conversation explores Dr. Thebaud’s journey into research, the importance of mentorship, and the challenges of translating research into clinical practice. They discuss the significance of recognizing opportunities, navigating critical feedback, and the promising mechanisms in regenerative medicine that could enhance lung repair in preterm infants. Dr. Thébaud discusses the innovative use of mesenchymal stromal cells in lung therapy for neonatal patients. He shares insights on the unexpected findings from his research, the potential of umbilical cord-derived cells, and the future of neonatal lung regenerative medicine. The conversation also touches on the importance of mentorship, resilience in research, and fostering a positive lab environment.

Link to episode on youtube: https://youtu.be/d0w0ln9uLpw

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Short Bio: Dr. Bernard Thébaud is a clinician-scientist with a focus on the clinical translation of stem cell-based therapies for lung diseases. Dr. Thébaud is a senior scientist with the Ottawa Hospital Research Institute (OHRI) and Children’s Hospital of Eastern Ontario Research Institute (CHEO RI), and a neonatologist with the Children’s Hospital of Eastern Ontario (CHEO), where he provides care to critically ill newborns. He is a Professor of Pediatrics at the University of Ottawa, uOttawa Partnership Research Chair in Regenerative Medicine and holds a Tier 1 Canada Research Chair in Lung Stem Cell Biology and Regeneration.

Dr. Thébaud obtained his MD at the University Louis Pasteur in Strasbourg, France in 1991 and trained in pediatrics and neonatology at the University Paris V in Paris, France, where he also obtained his MSc and PhD. He then completed a 2 year postdoctoral fellowship at the University of Alberta.

Dr. Thébaud has participated on numerous peer reviews committees and scientific advisory boards at the international, national and provincial level, including NIH and CIHR. He has over 120 peer-reviewed publications, and given over 80 lectures at leading international meetings and institutions in the past 5 years. He was a Canada Research Chair from 2005-2012. He received the “Rising Star in Perinatal Research” award from the CIHR Institute for Human Development, Child and Youth Health in 2008, and the “Best in Current Canadian Child Health Research” Sanofi Pasteur Research Award in 2007.

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Featured Manuscripts From Dr. Thébaud

Deguise MO, Thébaud B. The Role of Mesenchymal Stromal Cells in the Treatment of Bronchopulmonary Dysplasia: A Multi-Prong Approach for a Heterogeneous Disease. Compr Physiol. 2025 Aug;15(4):e70038. doi: 10.1002/cph4.70038. PMID: 40853849; PMCID: PMC12377523.

Cyr-Depauw C, Mižik I, Cook DP, Lesage F, Vadivel A, Renesme L, Deng Y, Zhong S, Bardin P, Xu L, Möbius MA, Marzahn J, Freund D, Stewart DJ, Vanderhyden BC, Rüdiger M, Thébaud B. Single-Cell RNA Sequencing to Guide Autologous Preterm Cord Mesenchymal Stromal Cell Therapy. Am J Respir Crit Care Med. 2025 Mar;211(3):391-406. doi: 10.1164/rccm.202403-0569OC. PMID: 39586004.

Renesme L, Lesage F, Cook DP, Achuthan A, Zhong S, Hänninen SM, Carpén O, Mižik I, Thébaud B. A Human Single-Nuclei Atlas Reveals Novel Cell States during the Pseudoglandular-to-Canalicular Transition. Am J Respir Cell Mol Biol. 2025 Oct;73(4):500-516. doi: 10.1165/rcmb.2024-0244OC. PMID: 40198804.

Cyr-Depauw C, Cook DP, Mižik I, Lesage F, Vadivel A, Renesme L, Deng Y, Zhong S, Bardin P, Xu L, Möbius MA, Marzahn J, Freund D, Stewart DJ, Vanderhyden BC, Rüdiger M, Thébaud B. Single-Cell RNA Sequencing Reveals Repair Features of Human Umbilical Cord Mesenchymal Stromal Cells. Am J Respir Crit Care Med. 2024 Sep 15;210(6):814-827. doi: 10.1164/rccm.202310-1975OC. PMID: 38564376.

Möbius MA, Seidner SR, McCurnin DC, Menschner L, Fürböter-Behnert I, Schönfeld J, Marzahn J, Freund D, Münch N, Hering S, Mustafa SB, Anzueto DG, Winter LA, Blanco CL, Hanes MA, Rüdiger M, Thébaud B. Prophylactic Administration of Mesenchymal Stromal Cells Does Not Prevent Arrested Lung Development in Extremely Premature-Born Non-Human Primates. Stem Cells Transl Med. 2023 Mar 3;12(2):97-111. doi: 10.1093/stcltm/szac088. PMID: 36724000; PMCID: PMC9985113.

Lithopoulos MA, Strueby L, O'Reilly M, Zhong S, Möbius MA, Eaton F, Fung M, Hurskainen M, Cyr-Depauw C, Suen C, Xu L, Collins JJP, Vadivel A, Stewart DJ, Burger D, Thébaud B. Pulmonary and Neurologic Effects of Mesenchymal Stromal Cell Extracellular Vesicles in a Multifactorial Lung Injury Model. Am J Respir Crit Care Med. 2022 May 15;205(10):1186-1201. doi: 10.1164/rccm.202012-4520OC. PMID: 35286238.

Hurskainen M, Mižíková I, Cook DP, Andersson N, Cyr-Depauw C, Lesage F, Helle E, Renesme L, Jankov RP, Heikinheimo M, Vanderhyden BC, Thébaud B. Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage. Nat Commun. 2021 Mar 10;12(1):1565. doi: 10.1038/s41467-021-21865-2. PMID: 33692365; PMCID: PMC7946947.

Kang MH, van Lieshout LP, Xu L, Domm JM, Vadivel A, Renesme L, Mühlfeld C, Hurskainen M, Mižíková I, Pei Y, van Vloten JP, Thomas SP, Milazzo C, Cyr-Depauw C, Whitsett JA, Nogee LM, Wootton SK, Thébaud B. A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency. Nat Commun. 2020 Aug 6;11(1):3929. doi: 10.1038/s41467-020-17577-8. PMID: 32764559; PMCID: PMC7414154.

Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH, Aschner JL, Davis PG, McGrath-Morrow SA, Soll RF, Jobe AH. Bronchopulmonary dysplasia. Nat Rev Dis Primers. 2019 Nov 14;5(1):78. doi: 10.1038/s41572-019-0127-7. PMID: 31727986; PMCID: PMC6986462.

Augustine S, Avey MT, Harrison B, Locke T, Ghannad M, Moher D, Thébaud B. Mesenchymal Stromal Cell Therapy in Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis of Preclinical Studies. Stem Cells Transl Med. 2017 Dec;6(12):2079-2093. doi: 10.1002/sctm.17-0126. Epub 2017 Oct 17. PMID: 29045045; PMCID: PMC5702524.

Ionescu L, Byrne RN, van Haaften T, Vadivel A, Alphonse RS, Rey-Parra GJ, Weissmann G, Hall A, Eaton F, Thébaud B. Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. Am J Physiol Lung Cell Mol Physiol. 2012 Dec 1;303(11):L967-77. doi: 10.1152/ajplung.00144.2011. Epub 2012 Sep 28. PMID: 23023971; PMCID: PMC3532523.

van Haaften T, Byrne R, Bonnet S, Rochefort GY, Akabutu J, Bouchentouf M, Rey-Parra GJ, Galipeau J, Haromy A, Eaton F, Chen M, Hashimoto K, Abley D, Korbutt G, Archer SL, Thébaud B. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med. 2009 Dec 1;180(11):1131-42. doi: 10.1164/rccm.200902-0179OC. Epub 2009 Aug 27. PMID: 19713449; PMCID: PMC3269236.

Thébaud B, Ladha F, Michelakis ED, Sawicka M, Thurston G, Eaton F, Hashimoto K, Harry G, Haromy A, Korbutt G, Archer SL. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation. 2005 Oct 18;112(16):2477-86. doi: 10.1161/CIRCULATIONAHA.105.541524. PMID: 16230500.

Thébaud B, Michelakis ED, Wu XC, Moudgil R, Kuzyk M, Dyck JR, Harry G, Hashimoto K, Haromy A, Rebeyka I, Archer SL. Oxygen-sensitive Kv channel gene transfer confers oxygen responsiveness to preterm rabbit and remodeled human ductus arteriosus: implications for infants with patent ductus arteriosus. Circulation. 2004 Sep 14;110(11):1372-9. doi: 10.1161/01.CIR.0000141292.28616.65. Epub 2004 Sep 7. PMID: 15353504.

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

Misty Good (00:01.587) Hello and welcome back to At the Bench, the neonatal physician scientist podcast of The Incubator. I'm Misty Good, a neonatologist scientist and the division chief of neonatal perinatal medicine at UNC Chapel Hill. And today I'm interviewing with one of our amazing co-hosts, Dr. David McCulley. David, would you like to introduce yourself?

David McCulley (00:22.185) Thank you, Misty. Yes, my name's David McCulley. I'm a neonatologist and physician scientist here at the University of California in San Diego. I am a lung developmental biologist, and I'm very excited today to be able to co-host with you, Misty, and interview Dr. Bernard Thébaud, who has been willing to participate in one of our interviews. I know Dr. Thébaud's work, because he is an outstanding leader in lung biology, has also done work related to CDH (Congenital Diaphragmatic Hernia), which is my personal interest. And we're very excited to have you today, Bernard. Would you mind just giving an introduction about yourself and then we'll dive into some questions about the work that you're doing and what's inspired you.

Bernard Thébaud (01:05.058) Yeah, thank you very much for inviting me. I'm equally excited to participate in this session. So I'm a neonatologist at the Children's Hospital of Eastern Ontario. That's in Ottawa, Canada. And I'm also a senior scientist in the regenerative medicine program at the Ottawa Hospital Research Institute. And the focus of our research is on lung development, injury, and repair, and the goal of developing therapies from the bench to the bedside to improve neonatal outcomes. The success of our research, I think, stems now from promising cell therapies and gene therapies for neonatal lung diseases. I think it's the best job there is in the world, being a clinician scientist and it's a great privilege to do this job.

Misty Good (02:10.003) It is really the best job in the world. And could you share with our listeners how you got interested in your journey in medicine and science?

Bernard Thébaud (02:23.766) Yeah. So I got into research quite late. I did my MD program in Strasbourg in France. And then I moved to Paris for my pediatric residency and my neonatal fellowship, a great city to live in. But there was a lot of work and I didn't even realize how much I missed about Paris. And after my fellowship or during my fellowship, I started my interest for research. I did my master's and then a PhD. And it's during this last year of my PhD that I met my research mentor. He's an adult cardiologist from Canada that was doing a sabbatical in Paris.

And we got along quite well. And he invited me to do a postdoc in his institution. And this was something that I had not anticipated at all, doing a postdoctoral fellowship. I think in France, there is no neonatologist that has ever done a postdoc. And it was even for me a surprise that I was doing a full-fledged PhD. But during this PhD, I really discovered my passion for the research, and then doing a postdoc in North America was really exciting because it would have been the first time that I did research only without doing clinical work in parallel. And that was for me, I think, a critical step to one, experience North America and number two, experience a full-fledged research fellowship without distractions. And even though I had an amazing job waiting for me back in Paris after that postdoc in Edmonton of all places, I decided to stay in Edmonton because...

Bernard Thébaud (04:51.726) I understood the concept of protected time for research and I felt that this concept didn't exist in Europe and North America was the only place where you could actually do a clinician scientist career and have the protected time to do research. Edmonton at that time had a great environment to get started.

David McCulley (04:57.045) Yeah.

Bernard Thébaud (05:21.954) ...for an early career researcher. I had great mentorship from my basic research mentor, Stephen Archer. And I also had support from my department head, Yves Lacaze, my clinical division director, Janie Bernard. And it was really exciting for me to be in this environment because I had the support and they gave me good advice. For example, I wanted to do 50-50, 50% research, 50% clinical, because, well, I'm a clinician. And I was told very clearly that in order to succeed, I needed to have 75% protected research time. And in retrospect, again, one of the best advice I received, but also the only one that I should have received from my supervisors because it set me up for success. And then there were great stipends for early career investigators that helped to get launched. And so it was great to get started in that environment. So I stayed there for 12 years.

And then I realized that my research was going more and more into regenerative medicine. And I was missing the environment that was conducive to go the next step, more deeply into the basic science of regenerative medicine, but also doing the clinical translation, which became an absolute priority for me. And so this was really a two year process weighing the pros and cons of moving. And because moving is disruptive and so one has to be conscious about that and do it for the right reasons. And so this is when I then moved to Ottawa where there was already a great environment for regenerative medicine. There was a regenerative medicine institute.

David McCulley (07:33.609) Yes.

Bernard Thébaud (07:46.734) ...and basic scientists that could teach me about stem cells and regenerative medicine. And so it took me really three to four years to realize that, okay, this was the right move. All the circumstances were conducive to doing the clinical translation and getting the advice from basic scientists in the stem cell field. And so overall, it was the right decision, but it was disruptive.

Misty Good (08:33.949) How did you decide that you wanted to go into the stem cell regenerative medicine field? What led you to that initial curiosity?

Bernard Thébaud (08:47.032) Yeah. So this was an interesting meeting that I attended one year into my independent research career. It was a Gordon Research Conference. They have always excellent conferences, small audience, very focused research topic.

David McCulley (09:06.291) Mm.

Bernard Thébaud (09:16.882) And a full week immersed into that topic. And it was on wound repair, something that I was completely outside my field so far. And I had to travel all the way from the Canadian West coast to the US East coast. It was a full day of travel. And the session started in the evening. And I had started my journey at 4 a.m. in the morning. And I was really a bit tired. And then I sit in this first session and all I see is fruit fly larvae being dissected under the laser and to inflict some wounds. And I thought, okay, it's okay. And then after the third or fourth lecture where this was the still the go-to model, I thought, okay, what kind of conference did I choose to attend? Hopefully it will get better. And yeah, the whole week it was the same thing. And I came home and thought, what a waste of time. And then a week later, I started thinking differently, like my literature search changed. My search terms were different. And I said, whoa, what's happening here? And...

David McCulley (10:25.439) Huh.

Misty Good (10:25.895) Oh no.

Bernard Thébaud (10:39.934) And all of a sudden I realized that, okay, something had happened during this meeting and it guided me into more, what is out there? What is known in wound repair? What is known in regenerative medicine? Right. And this is how it started. And I was still not clear whether I should go this route because I was just at the beginning of my career and had still to learn about lung development. But it was really very exciting. I chatted with my mentor about it and he said, well, you should go for it. And so this is how it happened. But yeah, in the end, this was the best conference I ever attended.

Misty Good (11:29.939) It seems like it changed your whole career trajectory.

David McCulley (11:30.538) Wow.

Bernard Thébaud (11:34.412) Yeah, definitely.

David McCulley (11:36.475) That's an incredible story. What is it about lung development and repair, and then thinking about regenerative medicine, that you find so exciting? I know you've used this in the context of not only CDH (Congenital Diaphragmatic Hernia), but also BPD (Bronchopulmonary Dysplasia). And I'm wondering what is it about that that excites you?

Bernard Thébaud (11:57.57) So first of all, we have no treatments so far, right? So that's basically where the unmet need is. And this is really the goal is to find treatments that work. Bronchopulmonary dysplasia is something that is prevalent among the infants we care for in the NICU (Neonatal Intensive Care Unit). And most recently, I was really shocked to learn that in 1967, Northway described BPD. And when we look at the incidences over the decades, even though we've...

learned so much about neonatology and we are masters at keeping babies alive, the incidence of BPD has never changed. It remains at about 30%. And it is in every form really devastating for the baby and the parents. And then also for the health care system because this chronic disease really impacts all stakeholders.

And so the goal is to develop therapies that work. So far, there is only really limited options that are approved such as caffeine and vitamin A. And so we really need additional therapy options. And then the lung is such a fascinating organ because it's so precisely engineered. When I meet trainees and I tell them, look, each time you breathe, there's...

150 square meters of surface that are actually activated to allow these exchanges to occur. And that has to be protected from infectious agents and so on and so forth. So it's really mind blowing. And the development itself, I think, is one of the most, all development is mind blowing, but this is, it has been studied for now a long time and there are still so many unanswered questions.

It's a very exciting organ. And then for lung diseases, chronic lung diseases, we have no other treatments but lung transplant, which is a very serious surgery with limited success. So we need therapies. And I think with regenerative medicine, it's probably one of the organs for which regenerative medicine may work the easiest.

because in bronchopulmonary dysplasia, there is already the organ here. The organ is injured. It didn't develop the way it should have developed. But we don't need to regrow the organ, right? We just need to inject a therapy that will hopefully jump start healing and repair. And then the endogenous pathways of the infants body will take over and ensure proper development.

so I think that's really the idea. And if we can achieve this, then we can have a therapy that is acting like medicine and reverses the disease rather than a palliative treatment such as dexamethasone that decreases inflammation but doesn't really reverse the disease.

Misty Good (15:38.259) Yeah, I think that's such an important point. And you've already published some really exciting preclinical data. Can you share a little bit of that with us and then how that's going to translate to some of your current clinical trials?

Bernard Thébaud (15:53.794) Yeah, so in our preclinical models of BPD, and we work in the rodent models, but also in the large animal models, in both models, we were able to show that mesenchymal stromal cells are therapeutic. They improved lung alveolarization in babies that were exposed to hyperoxia. So hyperoxia was the injury. And these cells seemed to act through a host of mechanisms, but particularly they were anti-inflammatory, they were antifibrotic, and they had pro-angiogenic properties.

And as such, these cells could undo some of the damage that hyperoxia had caused. And then it became obvious for us that, well, if this works in the models, we need to try this in the most fragile population. And so for us, babies born very prematurely who developed BPD are not only a vulnerable population, but they're...

the worst disease. And if we can cure BPD in these infants, we can really cure anything and that is much less severe. So that's why we decided to try to translate this for preterm infants. And these cells, these cell therapies are already used for other conditions in children, for example, for graft-versus-host disease, already been used in adult conditions such as ischemic stroke or ischemic cardiac injury. So these cells, there was already a lot known about the safety of these cells.

And in adults, there were thousands of patients who had been given these cells. So I guess there was a clinical equipoise. And that's when we said, okay, we can give this a shot and launch a clinical trial, which is the Steminent trial. And...

Misty Good (18:10.887) Maybe you can explain just a little bit about mesenchymal stromal cells, where they're coming from, how we're isolating them, just for some of our trainees who may not be familiar with MSCs (Mesenchymal Stromal Cells).

Bernard Thébaud (18:24.142) Yeah, so these are cells that are ubiquitous. They are present in lots of tissue. they are...

multipotent cells. They can differentiate in several lineages. So usually they can differentiate in fat tissue, muscle tissue, or bone. And they are called stromal cells and not stem cells because they are beyond the embryonic stem cell phase. So they're called multipotent rather than pluripotent. And these cells can be isolated from a number of tissues.

The most common one is bone marrow. So bone marrow transplant has been done for a long time now and is a proven therapy. So isolating these cells from bone marrow is relatively straightforward. The umbilical cord also is a great source, or the umbilical cord blood. And so we can isolate these cells easily. And then if we grow these cells in a culture dish and we grow them in specific culture conditions, we can expand these cells and from one donor...

we can manufacture enough cells for thousands of patients. So that's the beauty also of this cell therapy. Now we mentioned umbilical cord blood. So there is also a public cord blood bank. And these cord blood banks bank cord blood that has been donated for mainly stem cell transplants, right? And...

But you only need the stem cells. So there is actually another part of the umbilical cord blood that is what we call the waste product. And this waste product contains mesenchymal stromal cells. And so what we do, we harvest these cells from the waste products and we actually grow them in the presence of this waste product. So we avoid the use of animal products because in other labs or in industry, some people grow these cells in fetal calf serum.

So this is the difference here. As you can imagine, in a neonatal intensive care unit, not all parents will be comfortable with exposing their kids to products derived from cow fetuses. So we decided from the get-go that we would grow the cells in human products. And so we used this waste product from cord blood. And because...

of the public cord blood bank, there are thousands of these units and they're available. So we have a product that we can really scale to accommodate lots of patients if it proves to be effective. So far we are doing well. So these stromal cells are very easy to use. The drawback of cells in general, and this is not specific to the MSCs, is that the cells have to remain frozen and thawed just before use.

So in the NICU setting, I not sure we can use these cells. But if we use the cells once and if there's really a therapeutic effect, then it's fairly easy to thaw the cells just before we need them. So I this is where we are at this point in time.

Misty Good (22:01.309) That's so exciting. And so you have open clinical trials for preterm babies at high risk for BPD?

Bernard Thébaud (22:10.51) Yes. So we have three trials ongoing. They're all phase one, phase two trials. So the goal of the phase one portion of the trial is to assess safety, which is our number one priority. And we need to make sure these cells are not doing harm. We did establish safety in several animal models. And so it was a very natural next step to then try to establish safety in infants.

And at the same time, we wanted to assess for some signals of efficacy. And as such, the endpoints that we have are traditional endpoints, right? It's survival and it's the need for supplemental oxygen at 36 weeks corrected gestational age. And then we also do follow up at two years of age and we do infant pulmonary function testing, which we're very excited about because that has not been done in previous BPD trials.

And so we'll be able to tell not only is there less need for supplemental oxygen, which is really a binary readout, right? So it's hard to see changes, but we will see actual changes in the physiology and anatomy of the lung. And in this whole cohort, we have now 140 infants, 123 of which have reached the primary endpoint.

We have started to follow up all these kids. We have already 98 of 123 who were followed at two years corrected age. We have already enrolled 63 infants who have undergone infant pulmonary function testing. It's a very high rate of participation. We were super excited about the willingness of the families to keep coming back. And the data will be super interesting. So we're still enrolling. It's going well.

So our trial is called HULK. It's H-U-L-K. So helping under-developed lungs with cells. So that's the acronym for that trial. And that's just one of the three cell therapy trials that are ongoing. Now the other studies that we have ongoing are in animal models, of course, but also one is testing gene therapy.

The gene therapy approach is specific to Congenital Diaphragmatic Hernia. This trial we don't enroll patients yet. We're planning to enroll patients. But the model, the animal models are really, really promising. And this approach is using a different organ than the lung, which is very interesting as well.

Because there's so much happening prior to birth when CDH actually causes the lung injury. What we then do is we inject the therapy into the amniotic fluid and we use the entire gastrointestinal tract, the GI (Gastrointestinal) system, to have the gene expressed.

And then we make use of the liver that is already in the thorax and the liver produces high amounts of the transgene. And then that transgene is exported all around. It's in the serum and it acts within the lung parenchyma and other organs. So it's a very elegant approach to deliver therapy to very immature fetuses. And that's what we're working on now.

David McCulley (25:49.599) That is really fascinating. one of the things I'm curious about is, so you describe, you know, the cells from bone marrow and cord and cord blood. And, you know, I'm just sort of curious, like, what's the difference? Does it matter where you get them from? And the potency might be different, or, you know, I'm wondering how you decided to pursue cord blood MSCs specifically for...

Bernard Thébaud (26:17.582) Yeah, so that's a very good question. This is a very intense debate among scientists working in this field. And the cells from different donors and different tissues may have some characteristics that are different. There is no consensus on whether one is better than the other. And the advantage of bone marrow is that it has been around much longer.

It's proven. We have donors. There are donor lists. And so in that sense, it's more straightforward. Now, the difficulty there is that if we want to have the exact same cell product for multiple patients, then we always need to go to the same donor because there are donor-to-donor variations. And as you may know, harvesting bone marrow is an invasive procedure. And so we can't do that for every patient.

And so the donor will be, the bone marrow will be harvested from the donor maybe once. And so we try to bank as many cells we can or generate as many cells as we can in order to have enough for multiple patients. Now another thing is we don't necessarily like to use adult bone marrow for preterm babies because these donors may be 30, 40, 50 years old, right? And so their cells may have aged.

And so then we thought, can we use cord blood? And cord blood is really attractive because it is a young product. And cord blood is ubiquitous, right? It's a by-product of birth. So we have potentially access to this tissue for everybody. And that's a really neat advantage. And in the long-term, we may be envisioning autologous cell therapies.

where we use the baby's own cells. Right now we are not there yet, but in our trials that we are running, we are using cell banks. So a single lot of cells is manufactured in order to treat multiple patients. And that is, I think, very important. to answer your question...

We don't think that cell source matters as much. It's more the way how you handle these cells, the quality management system that is critical. So whether your bone marrow cells or your cord blood cells are well cared for in the lab, that's the most important bit. And as you know, GMP (Good Manufacturing Practice) labs are under very serious scrutiny by regulators. And so these labs follow...

excessively rigorous quality management systems to ensure the quality of the cells. And also what we are learning as we go along is that the culture conditions need to be really well controlled. And so we are very careful that when we are manufacturing cells, we culture them in a defined way. We add reagents or media at very defined time points at a very controlled...

pH, temperature, humidity and so on and so forth. Because like with any other manufacturing process, if you control it carefully, then you have a very reproducible product. And I think that's the key, to have a product that you can manufacture in large numbers but always be the same.

David McCulley (30:03.487) That's fascinating. And then I'm curious about in vivo, once you've administered the cells to patients, do you follow up on like what cells are there? Where do they go? Like, how long do they persist?

Bernard Thébaud (30:17.282) Yeah, that's a very good question. So so far, all the data we have from all these studies on MSCs and which includes like thousands of patients now is that we can never track these cells much longer than about 48 hours. And it depends on the patient population. Some have tracked them a week or even a month. It's very, very uncommon.

So we think the lifespan of these cells is fairly limited. And so what we think is happening is that the cells are paracrine actors. They do something in their vicinity, in their environment. And so they kind of alert the body, right? They activate some pathways. And then we think that these activated pathways then cause the body to heal.

We do not think that the cells actually do the repair, right? That's a very important differentiation. And it is also important because of potential long-term adverse effects, right? If these cells stick around for 20, 30, 40, 50 years, what happens? Do they cause some trouble? Cause some unwanted effects? And so far we don't think that's the case because, well, we can't track them. Now, you know, there are still some people who claim that maybe in specific organs, you can find cells after weeks or even years. I think there is a lot of debate. The data is not, I think, very convincing for that. But in general, I think the cells are gone. And so then really the whole game is what have the cells left behind in terms of signals or how have they reprogrammed the local environment? And in my view, we need to find out what it is that the cells are secreting during those 48 hours. And then if we identify that thing and we can make it industrially, then we can have a synthetic product. And that's really, I think, the long-term goal. We are not there yet. There are many papers that have been published in this field that claim that they found the thing, right? But the reality is that when you give those things to the body, they don't last very long. So we have still a long way to go. And I think, you if we could understand how these cells act on the local environment, meaning the local tissue, but also act on the local immune system. So all these microenvironmental interactions, those are the aspects I think that are very poorly understood now. And once we understand them fully, then maybe we can engineer better cells that actually act much more precisely and only do what we want them to do and cause no unwanted effects. And...

David McCulley (33:20.969) Yeah.

Bernard Thébaud (33:27.884) Yeah, and maybe we can even optimize further how long the cells persist, right? So maybe they can be optimized so that they actually last longer and are more beneficial. Or maybe we need to give them only once and they do their job really well. So I think all these things are still unknown now.

David McCulley (33:51.615) That's fascinating. That's, I mean, I think as we think about like a disease like BPD where mechanistically we know there's issues with alveolarization and vascular development and, you know, thinking about how these cells could potentially be acting on that is very fascinating.

Bernard Thébaud (34:10.862) Yeah. And I think understanding the biology is critical because, you there's this translational gap that exists. know, Bourbeau described that very nicely, this valley of death, right? And where animal models are beautiful, but they're not humans, right? And... So the success that we've seen in the animals, and it's very robust, very reproducible, may not translate exactly like this in the human. And that's what we need to see now with our clinical trials. But also, if we just do the clinical trial and we show this works, it's wonderful, but we still don't understand why. So I think it's really critical that we keep studying the biology side-by-side with the clinical trial. because if we truly understand the biology, then we can fine-tune treatments so that they're even better. And I think that's really the key here.

Misty Good (35:14.611) I think that was such an important point is that, you know, we need both sides. We need the bench to bedside, but then at the bedside, we need to take those samples back to the bench and continue to refine and understand and advance the field. So I think that's such an important point. And you've shown this in such a wonderful example in your, your...

Bernard Thébaud (35:38.99) Yeah. And I think, you it's very nice to see now how modeling has changed in the, in the last, say 20 years, right? So when we started off, everything had to be done in animal models and mice was the, the gold standard. Right. And obviously mice have completely different lungs than humans, but this is the only way that we, that we had at that point in time. And so the translational gap is large.

And when you go from a mouse model into a, a preclinical large animal model, you already make a big leap. you know, a, large animal lungs are very similar to, to the human. but now the revolution is three-dimensional tissue cultures and particularly organoids have transformed the field because these are human cells. that are grown in a dish and grow in 3D fashion and recapitulate some of the development that the lung goes through in utero or ex utero, right? And so we can test cell therapy in an organoid and see if the cells act on the organoid to improve the development. And that's fascinating because we don't need... an animal anymore at this point, right? So we've taken out some of the steps there. And so in principle, we could make the development a little bit faster. But going back to the difference between mice and humans, there are some examples in the research field where interventions that are very promising in the mouse model, where they even improve survival, actually harmed babies in the subsequent trials. I think the super, the high dose of steroids is one example, or even vitamin A is another example where we were super excited because in the mouse model, exogenous vitamin A completely reversed the phenotype and BPD just went away. And then you give this to kids and nothing really happened.

David McCulley (37:57.715) Yeah.

Bernard Thébaud (38:08.334) Well, there was a little bit of signal of efficacy but that's the way it is, right? So, and that's the reason why in my, I think, translational approach, I really think it's critical that we get preclinical data from a large animal. And in our case we did a CDH model in the lamb model. We had a hyperoxia model in the lamb model. We did some studies in the piglet model.

And I think these complementary models that are much closer to the human, I think, do help to narrow that translational gap because the mouse tells you a lot about the biology, but it's very different. Whereas the large animal may not tell you as much about the biology, and we don't have that many tools to look at all these details in a lamb or a piglet but we can use it as a safety model. And as a safety model, it's very powerful because if you can show this therapy is safe, not causing trouble in a in large animal, then we can be a little bit more confident.

David McCulley (39:24.915) That's fascinating. mean, you know, one of the things that is so neat about what you do and, and you know, knowing like the people in your institution and having visited it, how much sort of like thinking around like getting to the clinic and doing clinical trials, but also learning basic biology, it sounds like your work really intersects nicely with that. And I'm wondering if there's a particular challenge or question that you're facing in your research right now that

Bernard Thébaud (39:53.57) Yeah, so the key challenge is, as I alluded to, like what the cells are doing and how can we find that? It's a big challenge. And so I think we need to be able to characterize the cells better. And so if we could somehow turn this into a clinically relevant method to isolate those cells or identify the cells, then that would be a game changer. Identifying potency assays, for example, so an in vitro assay that could predict how the cells will act in vivo, that would also be a game changer.

Yeah, and because there are these two fields that intersect is the one, the biology, but also the manufacturing, the bioengineering. I think we will see some exponential improvements over time. And I hope that we will find a close to ideal cell therapy. If I can use another analogy, because manufacturing is so important, and I have shown this several times before, when we think about cell phones and the very first cell phone that was developed that Michael Douglas was showing off in Central Park in the movie called Wall Street.

David McCulley (48:26.473) Yes.

Bernard Thébaud (48:26.702) So this was a big heavy phone that was doing one thing, a phone call, that was 1983. The first iPhone came out in 2007. So you see over 20 years to develop from the brick to the smartphone and this is just technology. Here we're talking about biotechnology, right? So identifying the cell that we are working with today, they are more similar to the brick and we still have at least 20 years to go to make a smart cell.

Misty Good (49:05.159) I love that. I love that analogy. It's so great. But I think, you know, we have so many early career investigators that listen and, you know, are trying to soak up all of, you know, this mentorship and knowledge that you're providing them. What advice would you give to them that are, you know, thinking about a career? Because I think when you're first starting out, it's a little bit daunting to say, okay, well, we may not see the fruit of this for 20 years or we may not be able to get to the clinic in 20 years. Like how do we help build their resilience to keep going? And I know for us, it's like, obviously do something that you're really excited about, but what advice would you share?

Bernard Thébaud (49:51.362) Yeah, you gave already lots of cues to follow the passion, right? But this is actually important because you mentioned also resilience, which is also an important guarantee for success, perseverance, right? That you can only muster if you have the passion, right? Because you don't even realize how resilient, yeah, perseverant you are because if you are so passionate about it, right, you just plow through the difficulties and overcome these obstacles. You don't realize you're working because you're following your passion, right? So this is the exciting part. It's equally critical to have a good mentor. We mentioned this already earlier because these people help you...

David McCulley (50:36.585) Mm-hmm.

Bernard Thébaud (50:50.222) ...to stay grounded, stay optimistic and provide you opportunities, open doors and help you when you feel that you're stuck. Staying alert, never forget to ask why, why are you doing this, right? It's a very uncomfortable question, but it's a critical question. If you have the courage to ask yourself that regularly, I think you can avoid going into the wrong direction and making sure you stay on track and you still pursue what you're really passionate about. And then that comes then to staying focused. And here again, pictures say a thousand words. Steve Abman mentioned the squirrel analogy, that you shouldn't be chasing squirrels. When you go on a walk with your dog, you see the dog's always like being excited. There's a squirrel. There's a squirrel. There's another squirrel. And so you shouldn't do this in research, right? Stay focused, pursue your line of investigation, but again, stay attentive. Be flexible enough to move on to opportunities, right? But yeah, definitely you should have the passion. This is something intrinsic. If you don't have it, it's very difficult to have the resilience to go through this because the route is difficult, right? But it is very exciting. And as I said, right from the start, it's the best job on earth. And doing this for babies is also a privilege, like setting them up for success right from the start.

Misty Good (53:17.585) It truly is. And it can have such an amazing impact on their whole trajectory. And I think that's what makes our field so exciting.

Bernard Thébaud (53:25.218) Yeah, yeah.

David McCulley (53:28.063) That was great, Bernard. Just one last question. So we try to end our recordings just with something that demonstrates our humanity. So we're just curious if there's something that you personally like to do or that your lab group likes to do for fun outside of work. It could be something you guys do together or anything that just is something you do outside of your research. It's a good way to take a break.

Bernard Thébaud (53:55.756) Yeah, so the one fun thing I think is that each of our projects has a superhero acronym. And so it keeps, I think it keeps people motivated. It also probably speaks to the pediatric nature of the lab. We remain kids. I think there's a reason why we choose this subspecialty. And so each of the projects has a superhero acronym. For example, the MSC trial that we started is called HULK. So H-U-L-K, Helping Under-Developed Lungs with Cells. And there are some others that I hope will see the light in the clinic in the next five years. One is the Avenger and one is Spider-Man. And I won't say more. You will see. You will see when it happens. Another thing is when younger students in the lab start doubting about taking the next steps in their project, they're hesitating to do this experiment. Yeah, after we discuss ad nauseam about the experimental design and so on and so forth, at some point you got to do it, right? And so that's also a light motif where we mentioned these two things on the whiteboard. So it becomes clear. Yeah, just do it.

David McCulley (54:04.789) Aw.

Bernard Thébaud (continuation) Everyone knows that. And the other one is impossible is nothing. And so it keeps the motivation high. And one last thing I forgot to say about the advice for new investigators, early career investigators, is to watch on YouTube the Steve Jobs commencement speech...

David McCulley (55:51.829) Motivation.

Bernard Thébaud (56:11.15) ...to Stanford University students in 2005. It's very motivating and it has lots of, I think, good advice for young people.

David McCulley (56:36.233) Bernard, just wanted to say thank you again for taking time to talk with us today. It was awesome to hear about what's motivated you to do the work that you're doing, the questions that you have worked on, and inspirational on the way from outstanding mentors and taking advantage of great opportunities. So thank you so much for taking time.

Bernard Thébaud (56:56.396) Yeah, thank you very much for inviting me and I hope that it will be fun and also inspirational for your audience.

Misty Good (57:06.317) Incredibly inspirational and thank you on behalf of all of our team but also the babies and their families who, you know, are waiting right for the next therapy that hopefully your team can bring us. So we appreciate all of your hard work and your team's dedication to this really important work. Thank you.

Bernard Thébaud (57:27.096) Thank you.