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#252 - 🔬At The Bench - How to Heal the Preemie Brain 🧠





Hello Friends 👋,

In this episode of the Incubator "At the Bench," we speak with Dr. Eric Benner, a neonatologist and physician-scientist at Duke University. Dr. Benner shares his path from an MD-PhD student with a background in Parkinson’s research to a passionate neonatologist driven by personal experiences in the NICU after his twin sons were born prematurely. He describes how these experiences inspired him to dedicate his career to studying neurologic outcomes in preterm infants, focusing on neural stem cells and ways to improve outcomes for children like his son who has faced neurologic challenges. Dr. Benner discusses his pioneering research on oxysterols in breast milk, which activate neural pathways, particularly the sonic hedgehog pathway, to promote brain development in preterm infants. His journey includes navigating the patent process, founding a biotech company, and persisting despite initial skepticism from the pharmaceutical industry. He emphasizes the importance of mentorship and collaboration, sharing practical advice for budding physician-scientists. Dr. Benner also highlights the need for palliative care in neonatology, inspired by his wife's work in palliative medicine, as an integral component of compassionate care in the NICU.

Some featured manuscripts highlighting work from Dr. Benner:


Some featured manuscripts highlighting work from Dr. Benner:


Adrian A. Epstein, Sara N. Janos, Luca Menozzi, Kelly Pegram, Vaibhav Jain, Logan C. Bisset, Joseph T. Davis, Samantha Morrison, Aswathy Shailaja, Yingqiu Guo, Agnes S. Chao, Khadar Abdi, Blaire Rikard, Junjie Yao, Simon Gregory, Kimberley Fisher, Rick Pittman, Al Erkanli, Katie Gustafson, Caroline W.T. Carrico, Bill Malcom, Terrie E. Inder, C. Michael Cotten, Trevor Burt, Mari Shinohara, Charles M. Maxfield, Eric J. Benner. Subventricular zone stem cell niche injury is associated with intestinal perforation in preterm infants and predicts future motor impairment. Cell Stem Cell 31, 467-483 e466. 10.1016/j.stem.2024.03.001 


Agnes S Chao, Pavle Matak, Kelly Pegram, James Powers, Collin Hutson, Rebecca Jo, Laura Dubois, J Will Thompson, P Brian Smith, Vaibhav Jain, Chunlei Liu, Noelle E Younge, Blaire Rikard, Estefany Y Reyes, Mari L Shinohara, Simon G Gregory, Ronald N Goldberg, Eric J Benner. (2023). 20-αHydroxycholesterol, an oxysterol in human breast milk, reverses mouse neonatal white matter injury through Gli-dependent oligodendrogenesis. Cell Stem Cell 30, 1054-1071 e1058. 10.1016/j.stem.2023.07.010.


Miriam Hernández-Morales, Koyam Morales-Weil, Sang Min Han, Victor Han, Kelly Pegram, Eric J. Benner, Evan W. Miller, Richard H Kramer, Chunlei Liu. Electrophysiological Validation of Ferritin-Based Magnetogenetics for Remote Control of Neurons. J. Neurosci. 2024 https://www.jneurosci.org/content/44/30/e1717232024.long


MR Hutson, AL Keyte, E Gibbs, M Hernández-Morales, ZA Kupchinsky, I Argyridis, KN Erwin, K Pegram, M Kniefel, PB Rosenburg, P Matak, L Xie, EE. Davis, N Katsanis, C Liu, EJ Benner. Remote Activation of Temperature-Gated Ion Channels in Neural Crest Confers Febrile-Associated Birth Defects. Sci Signal 10, eaal4055 (2017). doi: 10.1126/scisignal.aal4055.


Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H, Warner DS, Liu C, Eroglu C, Kuo CT. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 2013 May 16; 497 (7449):369-73. https://www.nature.com/articles/nature12069



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


Misty Good (00:01)

Hi and welcome back to At the Bench, the Neo-Phy Sci podcast of the Incubator. I'm Misty Good, and a neonatologist-scientist and Division Chief of Neonatology at UNC Chapel Hill. And I'm co-hosting today with Dr. Betsy Crouch. Betsy, would you like to introduce yourself?


Betsy Crouch (00:16)

Thanks, Misty. Yes, I'm Betsy Crouch. I'm a neonatologist, a neuroscientist, and a vascular biologist at the University of California, San Francisco. I run a stem cell biology lab here, and I'm grateful to be able to be a neonatal physician scientist. Today on this episode of the Incubator podcast At the Bench segment, we're interviewing Dr. Eric Benner, who has some really exciting work going on in his laboratory and also a pretty compelling personal story. So Dr. Benner, could you introduce yourself for our podcast?


Eric Benner (00:50)

Yeah, thank you both. My name is Eric Benner. I'm a neonatologist at Duke University. I also run a laboratory that looks at neural stem cells and how neural stem cells respond to various complications that are associated with preterm birth. And our hope is to figure out ways to improve the neurologic outcomes of babies born preterm.


Misty Good (01:19)

Fascinating.


Betsy Crouch (01:20)

Yes, thank you. Well, for our listeners, before we got started, we were just kind of warming up a little bit and Eric was saying that he had a personal encounter in the NICU. And that was one of the things that inspired him along this career trajectory. So Eric, do you mind telling our listeners more about that story?


Eric Benner (01:40)

Sure. I was an MD-PhD student and my PhD work was actually in Parkinson's disease, which is the opposite end of the age spectrum that we're working on here. And my wife, we met in medical school, and we got married around the time she finished medical school, and she was pregnant with our twin sons, and we were really excited about this. At 19 weeks into the pregnancy, she started feeling contractions and started with preterm labor. It terrified both of us. We were actually in Florida on vacation at the time and flew back early, and she was in the hospital from pretty much 19 weeks until she delivered at 28 weeks and two days. And so our sons ended up at 28 weeks in the NICU. I, as a medical student, had never even heard of a NICU before. And so, this was a brand new experience. I'll tell you, it was terrifying. And our sons had, in retrospect, a fairly benign course through the NICU, thankfully, but they had very different neurologic outcomes. I have a son, Ethan, who is doing great in college right now. He's a sophomore at UNC, and he is a chemistry major and is interested in research in the chemistry space. And my other son, Gavin, had a very difficult outcome. 



Eric Benner (03:34)

He has a lot of neurologic disability. He doesn't have much communication skills. He's got a very autistic-like phenotype. And so, it's been difficult watching these two trajectories. And it's probably one of the main things that drives my interest in doing research to try and improve the outcomes of kids like Gavin.


Misty Good (04:01)

That's a really compelling story, especially driving your research focus. I wonder if you could say for our listeners, because they're at all stages of their training and even some thinking about pursuing a career in research, what initially got you interested in wanting to be a physician-scientist specifically?


Eric Benner (04:24)

Yeah, so I would even have to back up even further than medical school. 


Misty Good (04:27)

Sorry about that. We're going back in time.


Eric Benner (04:29)

So, I went into the military right after high school. And my interest was actually, I love chemistry just like my son does. And I was looking at a career in either chemical engineering or chemistry. And medicine didn't really factor into my idea of what my future would look like for me.


Eric Benner (04:52)

I didn't come from a family that had physicians in it. So, after I joined the military, I became very close, had a close friend and we actually ended up dating at some point in time. Her name was Hanlie, and she was diagnosed with cancer during the end of our relationship and ultimately passed away from cancer. And at the time, I just decided to go into medicine at that point in time, but I was always really interested in chemistry and chemical engineering. Shortly after I started medical school, a funny story is that I was in gross anatomy, and we were only two or three weeks into medical school, brand new, and should be excited about medicine. And I thought, I have made a serious vocational error. You know, I was not enjoying medical school, and this isn't what I had envisioned. And so I...


Betsy Crouch (05:53)

You mean staring over a cadaver wasn't ideal. I mean, we all have such strong memories of that, right?


Misty Good (06:01)

Such strong memories.


Eric Benner (06:00)

Yeah, maybe it was some of that was factoring in somehow just subconsciously, and I didn't know it. But so, I had decided I'm still going to do medical school. But I'm going to go into maybe something like pathology and get back to research and just do research full time. And that was really my trajectory until our kids were born at 28 weeks. And I saw a lot of different things in the NICU. Thankfully, they weren't happening to our children. But I saw a kid whose mother we befriended (my wife and I), and her son developed necrotizing enterocolitis and had bilateral grade 4 IVH and ultimately ended up dying. And that was my first realization that the NICU existed. And that kids in the NICU had these brain injuries that, if he had survived that, would have affected him for the rest of his life. And that's really kind of what drove me kind of into this path. So, I was always like research upfront, like that's really how I envisioned my career. And then, I ended up getting pulled into medicine or neonatology through these different personal experiences.


Eric Benner (07:25)

And that's where I ended up today. And having said that now, I love being a neonatologist. I would have never guessed this, but I love the clinical side of neonatology. I love getting to know families over time and having that sort of relationship with families. And then I love the physiology of neonatology and the pathophysiology of neonatology. And it's just something where I really feel strongly that there's hope on the horizon. I feel like not just my own research, but other people in this field that are doing really amazing research. I just think it's a field that's going to change rapidly over the next 10 to 20 years and is already starting to change already. So, I feel really optimistic about it. I think it's a great field to be in.


Misty Good (08:17)

It is the best field to be in! And when we have dedicated neonatologist scientists like you both, I mean, the world is our oyster, to save the babies from all these diseases.


Betsy Crouch (08:33)

Eric, could you go into this a little bit? I think a question that I get sometimes is, what is your balance? What's your clinical time and your research time? And it's wonderful to hear how much you care about your patient interactions and your families. But it can be challenging to run a research program to the extent that you are running your research, a really high powered, high funded research program, and you also do dedicated, detail-oriented clinical work.


Eric Benner (09:06)

Yeah, it's so challenging. And I imagine it's a little bit different at every institution, especially when you launch your career. I was lucky enough to have one of my mentors, Ron Goldberg. He was a neonatologist himself and he established a neonatal-perinatal research institute that was funded through a family, a local family, whom I'm sure Misty has heard of and has interacted with, but it was the Brumley family. And Dr. Brumley was a neonatologist who tragically, most of, a lot of his family actually perished in an airplane accident in Africa. And they had set up, the remaining family had kind of set up a fund to help pediatric research.


And at the time that he passed, he was actually the Department Chair of Pediatrics in Georgia. And the way that that impacted me is that Ron Goldberg had this fund that he could use to support the early careers of researchers. And so, I got a lot of support from that fund and from the NPRI, the Neonatal-Perinatal Research Institute. And that really protected a lot of my time early on. And one of the reasons Ron Goldberg did that was because he saw some of the work that we were doing in the lab about oligodendrogenesis, and it's stimulating the production of these myelinating cells that could really potentially impact outcomes of preterm infants, you know, with all the myelin injuries that these kids have. And so, he really dedicated a lot of those resources to helping really launch my career and protect my research time in the process.


Betsy Crouch (11:11)

Yeah, I think we do need to just really give a shout out to our families for one thing. But also, I took care of a family recently whose baby passed away. And the mother wrote to me and said, I don't want another bouquet of flowers. Can we start to put some money into this so that other families will have different outcomes for their children?


And I was just so overcome by gratitude in the way that, you know, families are able to think about these, really sad events and catalyze them into legacies for their loved ones. So, yeah, I just thought it'd be good to take an opportunity to thank all of the families, all of our families in the NICU, but especially the ones who lose a child, which is something that we would never wish for anybody or family members.


Misty Good (12:07)

I think paying it forward is incredible, right? Like the ability to experience such loss, but then to be like, I don't want another family having to go through that. And then, catalyzing that emotion and keeping the spirit of their baby alive in any way that they know how - to pay it forward, move forward the science, I think is really important. I have deep gratitude for all of our family donors as well.


Betsy Crouch (12:10)

Yeah.


Misty Good (12:36)

Absolutely.


Betsy Crouch (12:36)

Yeah, I could talk about this for a while. We've gotten into this research a little bit because I think we all know that, we're dealing with really life and death issues in our research. And I think I wasn't sure if this was appropriate to discuss with our families. And so, I was very grateful to be able to work with HAND (Helping After Neonatal Death), which is a support group here in the Bay Area, and ask families directly. And, you know, some of them articulated that this is a way to maintain the legacy of their child and especially to get to talk about their child after their child's gone, who they miss terribly. And I think for all of our family members, thanks, Eric, for bringing us into this topic. I think one of our biggest privileges is to be there as a neonatologist, as Misty said, it really is the best job. We're there at the moment of birth, but sometimes we're there at the moment of death, and to honor both of those life transitions. 


So maybe we'll transition a little bit to talk about the specific cellular and molecular research going on in your lab. I'd love to know what inspired you to look at neural stem cells. I'll out myself a little bit and say that I did this as a graduate student too with Fiona Deutsch, who's now in Basel. So, I also have a lot of affection for the neural stem cell niche. Now, I do lot of more human brain stuff than mouse work.


Eric Benner (14:05)

Yeah, it was such a funny story. I feel like I have funny stories. Maybe they're only funny to me.


Misty Good (14:20)

No, it's part of your journey. It's important to discuss.


Betsy Crouch (14:22)

Yeah, there's guideposts along the way, right? And that's what I think is helpful for our listeners.


Eric Benner (14:22)

Yeah, so the research that I'll talk about today leading into it, how did I get on this path to study ultimately oxysterols, which are cholesterol derivatives that are found in human breast milk that activate a pathway, a molecular pathway in neural stem cells called the sonic hedgehog pathway. So I'll talk about that. 


Betsy Crouch (14:48)

Yeah, that's going to be our hashtag for this podcast. Hashtag oxysterols.


Eric Benner (14:53)

Yeah. I'll talk about that in a second, but a funny story of how I ended up here was, or how I ended up looking at these to begin with, was serendipity, really. I was a fellow and I was like in the first couple months of fellowship and there was, maybe I shouldn't mention their name because I don't know how they will respond to this, but I was talking to one of the faculty members who's still at Duke now, and he's a good friend now, but I was, a new fellow, and he asked me, what are you interested in doing research on? And I was like, well, you know, very naive. I said these neurologic outcomes in these kids; I want to do things and figure out ways to improve those outcomes and particular brain injuries like stroke and PVL and these white matter injuries. I'm hoping to develop therapies to try and to mitigate some of the effects of these types of brain injuries. And he looked at me, and he was smiling. He was kind of joking around. But he said, you know, we don't do novel drug development in neonates. We do hand me down drugs in neonates. And it was, so that's why I don't want to mention their name, because they didn't mean anything by it. They were being sarcastic. 


Misty Good (16:07)

That's a terrible thing to say.


Eric Benner (16:16)

They were talking about how they need to change  from their perspective. It's like, we need to change this, but right now this is all we do. And I went into my call room after that, and my shoulders slumped, and I was like, I have made yet another vocational error. What am I doing here? I'm never going to be able to develop a novel drug that this person's probably right. 


Misty Good (16:18)

Right.


Betsy Crouch (16:19)

Yeah.


Eric Benner (16:42)

Will the FDA even allow this sort of research to be translated? And especially if it's a neonatal specific brain injury where you can't do it first in adults and then have it trickle down into neonates.


Betsy Crouch (16:56)

Yeah, I mean, for our listeners, fast forward to the end, Dr. Benner's figured it out. So I cannot wait to talk more about this because, I think it is, it is a misplaced philosophy. How should we say this? Right; it's an incorrect philosophy. It's a misplaced philosophy.


Eric Benner (17:09)

It is.  


Eric Benner (17:15)

It is, and it has affected so much of what we're going to talk about today on so many different levels.


Betsy Crouch (17:18)

Yes. I can't wait because I am nowhere near your level of experience in terms of this. But, you know, we've tiptoed into thinking about therapeutics as well for germinal matrix hemorrhage. And I hate that question, which is, but how many patients are affected a year? And you're like, but do you know for how long they're going to be affected? And have you thought about the moral implications of a child? Like, no, they haven't.


Eric Benner (17:45)

Yeah. 


Misty Good (17:46)

Right. Especially if they do not have an affected child or family member, then it doesn't hit home as much.


Betsy Crouch (17:50)

Yeah.


Eric Benner (17:54)

So, shortly after getting back to that meeting, I'm in my call room, I'm depressed, I've made another vocational error, something I seem to have a knack for doing. And I started thinking, well, OK, so they're right. I thought at the time that they were right, it turns out that they weren't entirely correct. But I started thinking, how am I going to develop a therapy to improve these neurologic outcomes and how am going to do that in a way that I'm going to be allowed to go to a clinical trial in this? And I started thinking of what are things that babies are exposed to? Could we find endogenous molecules that could potentially be developed into a therapy? Clearly, breast milk is one of probably the most well-known thing that all babies are exposed to and formulas. Formula feeding is also something that they're exposed to. And if I could find a molecule that was, or a class of molecules that was in either of those compounds or in either of those substances, could I potentially develop that? And obviously, breast milk over formula was the lead because breastfeeding has already been shown to improve neurodevelopment and, you know, there's lots of even really good papers, not all the papers that look at breastfeeding and neurodevelopment are top quality papers, but there were some really good ones that actually controlled for socioeconomic status and stuff like that. 


Betsy Crouch (19:34)

Yeah, can we hang out here for a minute and just talk about the evidence on which you were basing your hypotheses? Because I think this is another good practice to model. I was just reminding myself about your impressive body of research. And I was conflating Misty and you because I was like, breast milk, NEC. No, wait, breast milk, neurodevelopment.


Misty Good (20:01)

Right, well, breast milk and NEC, definitely, but also neurodevelopment.


Betsy Crouch (20:05)

Yeah, and like, it though? I mean, clearly, you know, there's the breast milk, decreasing the risk of NEC, which improves neurodevelopment. But I guess what was the evidence there? You know, you thought that the oxysterols would go directly to neurodevelopment before you before you tested it.


Eric Benner (20:22)

Yeah. So at this point, I wasn't even thinking about oxysterols at this point. I was just thinking about breast milk and there was a paper and I apologize. I don't remember the author, the authors on the paper, but it was a paper that showed using MRI at various stages after the baby's born, going out pretty far, they actually looked at myelination and myelin integrity.


Eric Benner (20:51)

And they were actually able to show that the longer kids were breastfed, the better myelin architecture on MRI that they were able to see. And that was one of the papers that really kind of stood out there. And remember, at this point, I'm just thinking there's got to be something in breast milk that is enhancing this myelination and neurodevelopment. And if we could identify what that is, could we turn that into a medication to give to kids who need it after a brain injury and stuff like that. And serendipitously, once again, there was a paper that came out in Science in 2006, 2007, that showed that oxysterols activate the sonic hedgehog pathway. I didn't know if oxysterols were in breast milk at that point in time, but I knew that were millimolar concentrations of cholesterol were in breast milk oxidized, cholesterol are just oxidized forms of cholesterol. So wherever cholesterol is, there's almost certainly going to be oxysterols there. And so, over time, we ended up doing mass spectrometry on human breast milk, and we identified these different oxysterols, and we actually identified about seven different oxysterols that were present in breast milk.


And it was already very well known that sonic hedgehog signaling in the neural stem cell population was, one of the drivers for oligodendrocyte fate specification in cells and neural stem cells. And so that's how I ended up actually kind of zeroing in on these oxysterols and it turns out that we screened breast milk, and found a number of oxysterols, and then we went into in vitro assays and started screening.


These were not cholesterols that we were isolating from breast milk, but cholesterol oxysterols that we were buying and or having synthesized. And then, we put those into these screens to look at oligodendrocyte differentiation from in vitro neural stem cell cultures. And we were able to identify four different oxysterols that were pretty potent in inducing oligodendrogenesis in vitro.


And then I actually worked with some immunologists here on Duke's campus. And we actually screened those same oxysterols against different inflammatory pathways. And we found an oxysterol that both inhibited various types of inflammation, inhibits TH17 polarization, inhibits NF-kappa B signaling, and was one of the strongest promoters of oligodendrogenesis. And so that's where we kind of focused in on that oxysterol.


Misty Good (23:46)

And just to follow up on that, since this is the focus of your R01, but then also you had an amazing publication in Cell Stem Cell on this. I was wondering if you could talk a little bit more about your models, both in vitro and in vivo.


Eric Benner (24:02)

Yeah, so our in vitro models are pretty straightforward, pretty similar to everybody, you know, the neural stem cell models that people use in vitro. But what was unique about our lab was we developed a diffuse white matter injury model in neonatal mice. And there was a, there was a guy by the name of Jim Wynn. Misty, I know you know Jim. He and I crossed paths here at Duke. God, here's another funny story. So, on Halloween night, I was a fellow on call and I had a kid who had a spontaneous intestinal perforation, and Jim Wynn was on the next morning. And I don't think I was on service, but I was on call. And so I was kind of signing out to everybody. And I knew that intestinal perforations, whether they were associated with necrotizing enterocolitis and or associated with SIP (spontaneous intestinal perforation), were one of the strongest risk factors for subsequent diffuse white matter injury. This is, of course, something we can't diagnose in the NICU. It gets diagnosed later, but you know, the neurologic outcomes, it's such a huge risk factor, intestinal perforations in babies.


And we didn't have a good animal model of diffuse white matter entry. People had injected LPS and these kinds of things, but they weren't great models and they served various purposes. But we wanted something a little more clinically relevant. And I was talking to Jim that morning and he was like, man, I used to do this intestinal perforation model in neonates back when I was a fellow.


And he basically told me how he did it and gave me some of his publications. And we ended up coming back to the lab and we used that as a model system. But nobody had ever really looked at the brain in that model system. Jim was an immunologist and was interested in studying sepsis and septic shock. And so we started looking at the brains of these mice and in the periventricular zone, and ultimately, we figured out that in the periventricular white matter, we get hypomyelination and get diffuse white matter injury essentially in the same regions in this mouse that are primarily affected in babies. And so, we were able to use that animal model to ultimately test whether oxysterols can promote oligodendrogenesis in the setting of that complication and stuff. And so I think it has implications directly for kids who've perfed. It has implications for kids with necrotizing enterocolitis, but I think it also has implications for kids who are just septic. They don't have an intestinal perforation per se, or maybe they don't have necrotizing enterocolitis, but maybe they have a gram-negative rod sepsis or something like that. You know, these are kids that are also at extremely high risk. And I think that the mechanisms of brain injury in those settings are fairly similar, not identical, but I think that there's going to be use for this type of approach that extends beyond NEC and perforations, but into kids with inflammatory causes behind their white matter injury.


Misty Good (27:33)

Now that's a great story, such a great story.


Betsy Crouch (27:33)

Yeah. Yeah, it is a great story. I mean, it's a juicy topic.


Misty Good (27:40)

Yes.


Betsy Crouch (27:42)

Can I ask, this is a naive question, but like the mechanism that the inflammation is translated into the brain, these different regions? I mean that's a very broad question. Into the brain?


Eric Benner (27:52)

Yeah, so there was an oxysterol publication about a year ago that was looking at oxysterols and it was only looking at oligodendrogenesis and it was looking at a very narrow mechanism through sonic hedgehog signaling promoting oligodendrogenesis from this. What we kind of ignored in that paper was that these oxysterols actually act also through LXR signaling and LXR signaling suppresses inflammation. So stick a pin in that for just a second. We subsequently just published another paper that looks at subventricular zone injury in the setting of perforations. We were able to show in mice; we used the mouse model to understand what that injury looked like, but we were actually able to show in humans, human preterm infants with intestinal perforations, that they have this injury that shows up as echogenicity in the subventricular zone after a perforation. And about 40 to 50 % of kids who survive their perforation will go on to develop this injury. 


Betsy Crouch (29:02)

Can I ask a clarification about, like the anatomy is so interesting. And I think what's really beautiful about the work that you've been able to do is, you know, to really translate a mouse model where, I mean, it's quite controversial if humans have adult neurogenesis, right? We won't go there right now. That would be a hot topic. But I think what you've done beautifully is kind of thread the needle.


Eric Benner (29:21)

Yeah, it is. Yeah, that's why I love neonatology.


Betsy Crouch (29:32)

It is to say that let's take pieces of this that are relevant mechanistically and use that. So, could you elaborate a little bit more? Because I was looking at your pictures from that gorgeous Cell Stem Cell paper and like, it's the ganglionic eminences, right? Where they have increased echogenicity, right? I'm double checking my neuroanatomy. But so it's the ganglionic eminences, which we think are responsible for the majority of inhibitory neurogenesis.


Eric Benner (29:51)

Yes. Yeah.


Betsy Crouch (30:02)

But in the adult SVZ, it's also probably an inhibitory neurogenic niche. And is that the way that these two can be equated to one another?


Eric Benner (30:16)

I haven't really thought about that specific question. One of the things that I was going to go when you were talking about the anatomy, and what makes this really interesting is that we're just now beginning to explore the core a plexus and the core a plexus just sits there and floats right above that structure, right above the subventricular zone, the whole lateral wall of the ventricle. And what we found in mice is that the core a plexus just fills up almost immediately after we model intestinal perforation with inflammatory cells.


Betsy Crouch (30:25)

Yeah. Hmm.


Eric Benner (30:46)

So far we've kind of focused on monocytes and macrophages, but now we're actually looking at neutrophils and NK cells and innate immune cells. And their accumulation in that structure, when they come out and why anatomical, when you said anatomical, this is what it triggered in my head, is that when they come out of the choroid plexus, they come into the CSF and where do they land? They land right on the surface of the subventricular zone and they destroy the ependymal layer that is covering the subventricular zone. And we're trying to figure out exactly how mechanistically the ependymal cells are eliminated, but we do know that they're eliminated. And so one of the things that we think is happening is that the ependymal layer of the subventricular zone, 


Betsy Crouch (31:31)

Mm-hmm.


Eric Benner (31:42)

when you destroy that layer, it appears that you form this astroglial scar where those ependymal cells existed at one point in time. And those ependymal cells have lots of functions that regulate the niche activity, the subventricular zone niche activity. They regulate neurogenesis. They regulate the migration, the unique migration of neurons in that structure. And when you destroy that ependymal layer, all of that goes essentially sideways.


But one of the other things that those ependymal cells do is they form these tight junctions and they express very high levels of water channels, aquaporin 4 and stuff. And if you think about it, they're the barrier between the stem cell niche and the CSF. And the CSF has low protein and high free water content. And in the tissue, you have the opposite. And so we think that that barrier is important to keep too much water from coming into that structure. And when those cells are eliminated, you get free water that passes through what used to be the ependymal barrier, but is now just an astroglial scar without the same sort of barrier effect. And you get cellular swelling. So you have these cells inside that niche that we think are now swelling. And that's what gives you the echogenicity. Because when you have cells swelling, you get stiffer tissue and then the stiffer tissue reflects back the sound waves at a higher rate. And so that's where we think we're going with what is the cause of echogenicity? This is all unpublished stuff and hasn't been finalized yet. So maybe when we end up publishing this, we'll be wrong about that. That's always a possibility, but that's kind of where we're going right now. So it's the choroid plexus that becomes inflamed, captures all these activated immune cells.


Misty Good (33:25)

Exciting.


Betsy Crouch (33:33)

Yeah, that's fascinating. Mm-hmm.


Eric Benner (33:40)

Comes from the systemic circulation and essentially just deposits them right onto this structure that is critically important at this point in time in the development of the human brain.


Betsy Crouch (33:51)

Yeah, thank you so much for walking us through that. It's really interesting. But I think also, it's so exciting because the idea of targeting neural stem cells is pretty intimidating. But by looking at this pathway, you can think of different stages on which to intervene. And then it becomes more plausible and feasible. But we got pretty, I'll apologize that we went on a neural stem cell rant.


Misty Good (34:19)

Haha!


Eric Benner (34:20)

Ha!


Betsy Crouch (34:20)

But I really enjoyed it and I hope some of our listeners do too, but we can get back to oxysterols.


Misty Good (34:24)

No worries. I do have a question just while we're talking about some amazing science, and you've articulated the mechanisms, and I'm so intrigued by that really fascinating work. I want to just shift a little and talk about, you're so into these oxysterols, you have a patent for them and something that we like to talk about that we don't always get to talk about a lot is how was the process in obtaining a patent? Also I guess what are your next steps, if you want to talk about, Tellus therapeutics, and tell us a little bit about that.


Eric Benner (35:04)

Yeah, absolutely. The process of obtaining a patent through Duke University was simple. That part was simple anyways. We first filed an invention disclosure, I think it was in 2014, and that buys you essentially a year. My recommendation to anybody listening to this podcast who might be in the neonatal space or any space in medicine really. If you think you have something that is going to benefit the lives of patients, you really need to just have a conversation with your intellectual property office. Don't present the data at a meeting before you talk to them. And because it's so simple to protect your work, and I'll come back to why that's important here in a second, but it's really just a day. They'll fill out an invention disclosure,


They'll submit it, it'll be official, and then you can go on and present your data at a research conference. If you do it backwards, if you present the research at a research conference, that might sound great from an academic point of view. We're all in this to try and increase our knowledge of mechanisms and disease processes and stuff like that.


But if you are the person that just happened to find, make a discovery that is really going to be impactful, whether it's in the cancer space or the neonatal space, and you present that data at a meeting, it becomes prior art. Nobody can patent it. And as wonderful as academic research is, like if you can't patent it, you're never going to be able to develop it. Nobody's going to, you know, especially new molecules,


that haven't been in the clinic yet. It just takes so much money to bring those, to de-risk those molecules and to develop those molecules, to formulate those molecules and all of this stuff. And nobody's going to invest in that process if they're not protected. That's just the environment that we live in. And so, that's just part of capitalism. And what's really tragic is that people, I think, might be under the gun to get a grant or they need a new publication, or maybe they're a person like I was starting out, and you know, they're being told publish, publish, publish all the time. And sometimes you just need to take a breather and like go talk to them because this was something that I thought really early on was going to be something that could be translated. It was a lipid and breast milk that induced oligodendrogenesis and improved myelination.


Misty Good (37:46)

Awesome.


Eric Benner (37:47)

And if we didn't patent it, would just be another story in the journals that would go on in time. And just from that, that would be the end of it.


Misty Good (37:59)

So how did you then take it to a company or create your own company?


Eric Benner (38:03)

Yeah, so two things. I had no interest in developing my own company or starting a company in the very beginning. I was very hopeful that the professionals, you know, that the other companies that exist would just be so interested in this that they would absolutely want to develop this and help babies, right? Who doesn't love a baby? And so I was really kind of, I went, I met with our OLV office and talk to them about this process. And they basically just said, well, go out and start meeting with these people. Tell them, reach out and start talking to them and see if you can find somebody that's interested in it. And meanwhile, we'll post it on our website so that people who are looking for IP to potentially license will see it. And my experience was that I went to about 16 or 17 different companies.


They ranged in size, there are small companies in RTP, which is the research triangle park here in North Carolina, where all our biotech companies are. I talked to smaller companies. I talked to larger companies like GSK. I ended up talking to companies in Boston.


Ultimately, I got the exact same answer back. It was like they all huddled ahead of time and said, what, how are you going to respond to this guy? And what they said was like, wow, that, science is really exciting. The oligodendrogenesis and you know, it's, different than, everything that we have in our pipelines or whatever. but they said, you know, we just don't know or understand neonates, and we don't understand if a regulatory path even exists for you to develop novel drugs for babies. And if it does exist, it doesn't really matter because we don't have anybody in our company that has that sort of expertise. And so, if you want to develop this drug for multiple sclerosis, come talk to us. We'll be very interested in potentially doing that because we understand adults and we understand the regulatory path into adults, but we're going to pass on babies.


Betsy Crouch (40:21)

And sorry, why didn't you go that way? Because that was the first thought I had was like, sure, that's the way I can get this done. Go for it.


Eric Benner (40:24)

Yeah. Well, I'll tell you, there were moments when I was thinking that I might just have to do it that way, but...


Misty Good (40:29)

Yeah.


Betsy Crouch (40:34)

I mean, MS also, you know, also we're the opponent, you know?


Eric Benner (40:37)

But I was also worried in the back of my head, and I'm still worried today, that adults, that the mechanism is very weighted towards neural stem cells. And I think we all agree that in the germinal matrix and in the subventricular zone of a preterm infant, that there's an abundance of neural stem cell populations there that are potentially targets for this drug.


And when you get into the adult space, it becomes more controversial. And I'm not even going to say whether adult neural stem cells exist or not, because I don't want people screaming at me online. But I'm just saying it's controversial. And my biggest fear was that we would license this to somebody that would develop this for multiple sclerosis. They would go to a clinical trial of multiple sclerosis, and it would ultimately fail because the neural stem cell populations just aren't there.


Betsy Crouch (41:16)

Yeah, yeah, the mechanism is different.


Eric Benner (41:36)

And then, once you fail in multiple sclerosis, trying to raise money for a baby trial seemed to me impossible. And I actually had an opportunity to meet with Rob Califf back when he was, before he went back to the FDA, he was just here at Duke. And he just gave me, we met for like 45 minutes, and he just gave me some high level advice from his past experience with the FDA.


Betsy Crouch (41:47)

Good for you.


Eric Benner (42:04)

And one of the things that he really kind of drilled into me for 45 minutes was the FDA is really hungry for neonatal direct development. There's a huge unmet need across, you know, not just in the brain, but just across all systems in the NICU. Misty can tell you about NEC, right. 


Betsy Crouch (42:19)

Yeah.


Misty Good (42:28)

It’s all about the babies. We're trying to save the babies from NEC and yes, there needs to be a better path for babies.


Betsy Crouch (42:31)

Mm-hmm.


Eric Benner (42:33)

And so his response to me was that the FDA is really hungry for this and they're going to probably work with you if you can give them some data that you think you have some, molecule that's worthy of development here. They're not going to shy away from the fact that this is going to be babies. And then he also said, I said, well, I'm getting a lot of like, why don't we do this for multiple sclerosis? I explained to him my fears about the neural stem cell populations and what if this doesn't work in multiple sclerosis? And his response to me or his advice to me at that point in time was very simple. He was like, go into the population that you think is most likely going to respond to your drug. And the fact that it's babies, well, that just means that you're going to have to do some different drug development in neonatal specific animals. But if you complete that drug development, you do a good job there, de-risking this, the FDA is going to be a partner in helping you move this forward into babies. Right now, these brain injuries don't have a treatment, and kids who suffer from them are affected their entire lives. And so the FDA is going to absolutely want to be a part of developing a safe molecule that could impact these neurodevelopmental outcomes. So basically, what he was telling me was don't listen to the pharmaceutical companies that are afraid to develop something for babies.


Betsy Crouch (43:38)

Thank you.


Eric Benner (43:59)

If that's the population that you think is most likely going to respond to your drug, then work with the FDA and target that population. And that's ultimately what we did. Now we have new data suggesting that the oligodendrocytes might mature better in the presence of this drug, which does open the possibility for some efficacy in diseases like multiple sclerosis and stuff. But we're very close to a clinical trial now for babies. Our first clinical trial is going to be this spring or summer in healthy adult volunteers. That's really going to not only assess safety, but is also going to help us kind of nail down the dose that we're going to be targeting in human infants. We've done all kinds of PK studies in piglets, neonatal piglets, you know, to try and help us model the pharmacokinetics of this molecule in a neonate. But we really need to know and convince ourselves and, importantly the FDA that this drug isn't being metabolized in piglets differently than humans would metabolize this. And so we're ultimately going to end up using the pharmacokinetic data from neonatal piglets and healthy adult volunteers. And we have drug modelers here at Duke that are going to help us kind of identify what the most likely dose is going to need to be in a preterm infant.


Misty Good (45:32)

That's wonderful. So exciting, all the work that you're doing.


Betsy Crouch (45:36)

Yeah, congratulations and thank you for fighting the good fight, right?


Misty Good (45:43)

It sounds like you got great advice and even some mentorship along the way. I don't know if you want to talk a little bit more about the advice that you got along the way for listeners who may be in the thick of it and some words of encouragement for them?


Eric Benner (46:01)

Yeah, so, you know, after speaking to, people like Rob Califf and people here, one of the things I did was I had a meeting with my department chair, Ann Reed, who's the department chair of pediatrics here at Duke, and Dr. Colleen Cunningham, who is now I think at UC Irvine, I had a meeting with both of them. And I was, you know, by that time, I had some data on how receptive pharmaceutical companies were to this. And it seemed like they weren't very receptive to it. And both of them kind of just said, call the elephant in the room. And they were just basically like, look, if you're going to develop this molecule really needs to be developed for infants, and especially preterm infants, you're probably going to have to start a company to, at a minimum, de-risk this molecule to a point where maybe a pharmaceutical like Biogen, who was one of the companies that we met with actually early on, would eventually take it over. Because by then you would have interactions with the FDA. You could show them that the FDA was supportive, that there was a regulatory path that exists. If you do these things, you can go to a clinical trial and babies. Once you get it to that point, you're going to essentially de-risk some of the major risks associated with this and you're going able to move it on. And so, eventually, I started this company, I co-founded this company with a guy by the name of Jason Kralic, who is a PhD, a neuropharmacologist by training, but he had spent essentially his whole professional life in the drug industry. He was working for GSK; he was working for a lot of these pharmaceutical companies. The bulk of his career was spent at GSK. And so he had the industry side experience that I did not have. And to be fair and honest, I didn't really know at that point in time that I wanted to have, you know, I wanted somebody to do this drug development for me, essentially. And working with Jason has been incredible because I mean, he's a wonderful human being. He sacrificed a lot to help this drug go to the clinic. He loved the idea of helping babies and preventing cerebral palsy and some of these other negative effects of these types of brain injuries. And he essentially quit his job and lived trying to get this company funded. And he and I traveled around the country. And so this is what I'll say to people.


It sounds, the front part of the story sounds discouraging because we were meeting with investors and we were getting almost the exact same. So it was like the pharmaceutical companies called the investors and said, here's what you say when this guy comes to your door because it was the same, same sort of thing. Like the investors, were, you know, very interested. A lot of the investors were interested in myelination and the multiple sclerosis space. And we were showing them this in vivo data that we can improve myelination. And they were, again, they were just like, just kids, really babies, I don’t know, does the FDA even allow that, you know, and stuff like that. People were very negative, so it was really hard for a long time to find funding to be able to fund this company. But there are investors out there for everybody, and you just have to find the right investor. And we ended up meeting up with a group called Xontogeny.


Chris Garabedian is the head of Xontogeny, but he was kind of the lead person we were talking to. And what made him unique was that he had an experience in pediatric rare diseases. And so he loved working in that space because he really loved the idea of improving the lives of children. He really is like that genuine nice guy, which was an important part to have in the investor, somebody who wanted to put the time and effort into making this work. And he was driven by that. And he also, you know, was the CEO of Sarepta, which was one of the first companies that developed a myotonic dystrophy drug for a while. So he had an appreciation and an understanding of how, how difficult this would be and how different this would be from your typical drug development path.


Misty Good (50:23)

Yes.


Eric Benner (50:46)

And they were the ones that seed funded us and got us to this FDA pre-IND meeting. And then once we had that meeting and the FDA kind of enthusiastically endorsed our, like they were excited about this. And as a matter of fact, offered to like, if we need help, if we have questions, just send us some, we'll do our best to kind of answer questions for you along the way. We recognize that this is a patient population that most people are not developing drugs for. So it's you know, being the most vulnerable patients in the hospital, of course, they just want to make sure that it's done right. So they've been incredibly helpful, but that kind of showed through our pre-IND meeting. And then once we had that pre-IND meeting in hand, then we were actually able to raise the money, the sizable amount of money that's needed to bring a drug literally from the laboratory into the clinic. And it was really that Xontogeny group, not only having an interest and faith in what it was that we were trying to do, but they brought in drug experience know-how that helped us kind of, or very much helped us navigate that pathway. 


Betsy Crouch (52:06)

What an inspiring story.


Eric Benner (52:07)

So there's people out there that are interested in neonatal medicines and drug development. It's just a little bit harder to find them, but they do exist. When you find them, they're incredibly helpful.


Misty Good (52:21)

That's great.


Betsy Crouch (52:23)

Yeah, I really enjoyed that story about your journey, but thank you for your resilience, your determination, your perseverance. It seems like all of those qualities have been required. Maybe in the interest of time, we'll just have to wrap up now. And we like to potentially end on something fun, like, are there things that you enjoy when you have free time? What does your lab do for fun? Is there a cool tradition that you've started in your lab that you'd want to share with our listeners?


Eric Benner (53:03)

Well, before we get into the fun topic, can I take us to the opposite end of that spectrum? And one of the things that I wanted to talk about today that I think that would really be a huge game changer for neonatology is palliative care. And I say this because my wife is a palliative care doctor here at Duke. She is all adult. Like she is not on the pediatric side, but I will tell you that having conversations with her every night about the kind of medicine that they practice on the adult side in the palliative care world has impacted the way that I interact with families here at Duke. And I just think that having more neonatologists that might do a palliative care fellowship or even just work with a palliative care team at their university to learn these incredibly important skills of how to talk to families and how to navigate some maybe not desirable outcomes in the NICU and how much I think that that can change the lives of these kids, both those that survive and then maybe some that are kind of ultimately end up dying in the NICU, but they do it with a little bit of more dignity and the family has a little bit more control over that situation or whatever.


I know you wanted to talk about something fun and that's all I wanted to do was just plug in, like that's something I think the NICU is a desperate need of is more exposure to palliative medicine and how to have those difficult conversations with families.


Betsy Crouch (54:49)

Yeah, I mean, thank you for taking the time to plug that because this conversation has been a nice illustration of how, you know, the whole point is to go from molecules, from oxysterols to people, right? And, you know, that there are different skill sets that we need to be open to at a minimum and maybe sometimes take on ourselves. Thank you for all your time.


Eric Benner (55:02)

Yeah.


Eric Benner (55:14)

Yeah. With getting back to the fun stuff. So I grew up in California and I grew up surfing. I grew up in St. Clemente, you know, two blocks away from the beach. And one of the reasons why I moved to North Carolina was that surfing and the beach was only two and a half hours away. And so, I still like to surf. I've taught my kids how to surf. I will say that since the pandemic, they haven't been able to surf all that much. So we're hoping to get back into it. But I love surfing. I used to ride short boards. I'm more of a long boarder now. That has changed. I was sad about that for a while, but I think that's more my thing at this stage of life.


Misty Good (56:05)

Betsy, do you surf? I don't surf as a previous Californian.


Betsy Crouch (56:07)

No, I mean, it's really, this was kind of a funny story. I was doing a neonatal transport, you know, recently. I still do that. Yeah, you know, I was an EMT growing up, and there's something about transport medicine that still excites me. I’m also fine working on a grant in the back of an ambulance.


Misty Good (56:19)

You still do them. Wow.


Eric Benner (56:31)

Yeah.


Misty Good (56:32)

My god, I would get so carsick.


Betsy Crouch (56:34)

I was in the back of this ambulance, and I was just realizing that that was the least cool person there by far. Like my two nurses, one was a surfer and one was an open water swimmer. And, you know, there's just a level of dedication in the Bay area to water sports because the water is not an enjoyable temperature, I think. Anyway, not to shame her for that, but yeah, I'm not, I have not ventured into that.


Eric Benner (56:56)

No.


Misty Good (57:02)

I'm not either, but it's great that you are, Eric. Are you going to take your lab surfing at some point?


Eric Benner (57:08)

I am not sure if they would, or how much they would like that.


Betsy Crouch (57:12)

Yeah.


Misty Good (57:14)

You need to go to like a conference somewhere where they're surfing and get your whole lab there.


Betsy Crouch (57:19)

Well, PAS is in Hawaii, right?


Eric Benner (57:19)

Yeah, that's what I heard and we're planning on going this year. And we have friends that live in Hawaii. So yeah.


Misty Good (57:21)

That's right. There you go. That's your opportunity to do it.


Betsy Crouch (57:29)

Yeah, yeah, that's taking the trust fall to the teamwork activity to a new level.


Eric Benner (57:36)

I went to the Human Milk Institute conference last year, and it's always in the same spot. It's in Scripps in La Jolla. And I walked out during a break, and you walk outside the sliding glass doors from the conference area, and it's La Jolla Beach right there, surfing. And so I thought, if I ever come back to this conference, I am 100% bringing a surfboard. And I just might surf the whole time.


Betsy Crouch (57:53)

Hmm.


Misty Good (58:04)

That's amazing.


Eric Benner (58:05)

It's literally like outside the glass door, there's a patio, some grass, and then the sand.


Misty Good (58:12)

That's great. Well, doing science is like surfing, right? It's kind of the same highs and lows.


Eric Benner (58:18)

Yeah, you spend most of the time falling down, but every once in a while, you get a great wave, and it's an amazing experience. 


Betsy Crouch (58:19)

It is a wild ride. So yeah. 


Eric Benner (58:34)

Those failed experiments all the time, and then finally you stumble across something like an oxysterol that induces oligodendrogenesis, and you're just like super cool.


Misty Good (58:42)

That's fantastic. On that note, we are really grateful for you coming on the podcast and allowing us to interview you today and hear about your inspiring journey of resilience and all the incredible work that you're doing. So thank you so much for that. We appreciate it.


Betsy Crouch (58:44)

On that note. Thank you.


Eric Benner (59:03)

Thanks for inviting me to do this. It was fun and thanks for your interest in oxysterols.


Misty Good (59:12)

Yeah, I think Betsy and I are going to talk to you offline about collaborating.


Betsy Crouch (59:15)

All right, thanks to our listeners as well for tuning in and we'll catch you next time on the At the Bench segment of the Incubator.



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