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#145 - NEC SYMPOSIUM 2023 - 👩‍⚕️ Dr. Gail Besner MD


Gail Besner Incubator Podcast

Hello Friends 👋

We are recording live from the 2023 NEC Symposium. We are excited to kick things off with an exciting interview of Dr. Gail Besner, chief of pediatric surgery at Nationwide Children's Hospital. We will be streaming live on twitter (check out our profile page - https://twitter.com/nicupodcast) and posting a number of episodes and short interviews throughout the duration of the conference.

Let's build a world without NEC!

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Gail Besner MD: Chief of Pediatric Surgery at Nationwide Children's Hospital. She is also a Principal Investigator in the Center for Perinatal Research at The Research Institute at Nationwide Children's Hospital and Associate Program Director of the Pediatric Surgery Residency program. She also holds the H. William Clatworthy Jr. Professorship in Surgery at The Ohio State University College of Medicine and is a Professor of Surgery and Pediatrics at The Ohio State University College of Medicine.

The transcript of Gail's interview can be found below:

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Find below some of the articles mentioned by Dr. Besner:


Next-Generation Probiotic Therapy to Protect the Intestines From Injury.Ragan MV, Wala SJ, Goodman SD, Bailey MT, Besner GE.Front Cell Infect Microbiol. 2022 Jun 28;12:863949. doi: 10.3389/fcimb.2022.863949. eCollection 2022.


Antibacterial and anti-inflammatory effects of Lactobacillus reuteri in its biofilm state contribute to its beneficial effects in a rat model of experimental necrotizing enterocolitis.Shelby RD, Mar P, Janzow GE, Mashburn-Warren L, Tengberg N, Navarro JB, Allen JM, Wickham J, Wang Y, Bailey MT, Goodman SD, Besner GE.J Pediatr Surg. 2022 Jul;57(7):1382-1390. doi: 10.1016/j.jpedsurg.2021.09.001. Epub 2021 Sep 20.


Lactobacillus reuteri in its biofilm state promotes neurodevelopment after experimental necrotizing enterocolitis in rats.Wang Y, Jaggers RM, Mar P, Galley JD, Shaffer T, Rajab A, Deshpande S, Mashburn-Warren L, Buzzo JR, Goodman SD, Bailey MT, Besner GE.Brain Behav Immun Health. 2021 Jul;14:100256. doi: 10.1016/j.bbih.2021.100256. Epub 2021 Apr 6


Lactobacillus reuteri in Its Biofilm State Improves Protection from Experimental Necrotizing Enterocolitis.Al-Hadidi A, Navarro J, Goodman SD, Bailey MT, Besner GE.Nutrients. 2021 Mar 12;13(3):918. doi: 10.3390/nu13030918.


A novel probiotic therapeutic in a murine model of Clostridioides difficilecolitis.Shelby RD, Janzow GE, Mashburn-Warren L, Galley J, Tengberg N, Navarro J, Conces M, Bailey MT, Goodman SD, Besner GE.Gut Microbes. 2020 Nov 9;12(1):1814119. doi: 10.1080/19490976.2020.1814119.


An enhanced Lactobacillus reuteri biofilm formulation that increases protection against experimental necrotizing enterocolitis.Olson JK, Navarro JB, Allen JM, McCulloh CJ, Mashburn-Warren L, Wang Y, Varaljay VA, Bailey MT, Goodman SD, Besner GE.Am J Physiol Gastrointest Liver Physiol. 2018 Sep 1;315(3):G408-G419. doi: 10.1152/ajpgi.00078.2018. Epub 2018 May 31


Harvesting the benefits of biofilms: A novel probiotic delivery system for the prevention of necrotizing enterocolitis.Olson JK, Rager TM, Navarro JB, Mashburn-Warren L, Goodman SD, Besner GE.J Pediatr Surg. 2016 Jun;51(6):936-41. doi: 10.1016/j.jpedsurg.2016.02.062. Epub 2016 Mar 2.PMID: 27032609

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


Ben Courchia MD:

Hello, everybody. Welcome back to the Incubator podcast. It is Monday. We are at the NEC symposium and we are very excited to bring you some of the speakers that are featured at today's NEC Society Symposium. Daphna, how's it going today?


Daphna Yasova Barbeau, MD (she/her):

Well, we've been really looking forward to this trip and to meet with some of the, uh, you know, wonderful people that are working so hard at the neck society. Um, and certainly with, with collaborative collaborators that are. Move moving the, moving the field forward. Right. So the,


Ben Courchia MD:

Mm-hmm.


Daphna Yasova Barbeau, MD (she/her):

the goal is a world without neck. So


Ben Courchia MD:

That's


Daphna Yasova Barbeau, MD (she/her):

we can't


Ben Courchia MD:

right.


Daphna Yasova Barbeau, MD (she/her):

wait


Ben Courchia MD:

That's


Daphna Yasova Barbeau, MD (she/her):

to


Ben Courchia MD:

right.


Daphna Yasova Barbeau, MD (she/her):

hear more.


Ben Courchia MD:

And we are very excited to bring you today, Dr. Gayle Besner. I know I know Jen Canvasser said we have to go on a first name basis, but at least for at least while I'm introducing you, Dr. Bestner, I'm going to want to call you Dr. Gayle Besner, and then we can go on a first name basis after that. Dr. Gayle Besner is the chief of pediatric surgery at Nationwide Children's Hospital. She is also a principal investigator in the Center for Perinatal Research at the Research Institute at Nationwide Children's Hospital. and Associate Program Director of the Pediatric Surgery Residency Program. She holds the H. William Clattworthy Junior Professorship in Surgery at the Ohio State University College of Medicine and is a professor of surgery and pediatrics at the Ohio State University College of Medicine. Gail, thank you so much for making the time to be on with us today.


Gail Besner:

My pleasure, Ben and Daphna. Thank you so much for the invitation.


Ben Courchia MD:

No, thank you. Thank you for making the time. And so I wanted to maybe start this conversation by asking you, what is it that you are talking to us about today at the NEC Symposium?


Gail Besner:

So we're going to be talking about a novel therapeutic strategy for necrotizing enterocolitis. And it's a medication, a medical strategy, which might sound odd coming from a surgeon, because as you noted, I am the chief of pediatric surgery at nationwide children's hospital, but I'm a firm believer that necrotizing enterocolitis really should not be considered a surgical disease. And I feel very strongly that it's a disease that should be prevented with a therapeutic regimen, perhaps including novel medications in order to prevent neck. And the reason that I think that that's so important is because there are varying forms of neck, but in its most aggressive form, you can start with a prematurely born baby, or sometimes even a full-term baby, perfectly fine at noon and by 6 p.m. can be dead from necrotizing enterocolitis.


Ben Courchia MD:

That's true.


Gail Besner:

And so, given the incredible aggressiveness that the disease often presents with, it makes a lot of sense to me to prevent the disease before it occurs, rather than trying to catch up after the disease has already occurred. And... You know, to become a pediatric surgeon, you have to first become a general surgeon, and then you do specialized training in pediatric surgery. And I did that training between 1989 and 1991. And as a first year pediatric surgery fellow in 1989 in the fall, just a few days after I started, we were consulted for a premature baby in the neonatal intensive care unit named Baby Boy Lewis. And he weighed 1900 grams at that time, which in those days was considered really, really


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

small, not so much in these days because we can keep babies that are 300 to 400 grams alive now. But in those days, he was really quite small and he had necrotizing enterocleitis and we had to operate. And so I remember vividly doing the operation. and we were able to save enough of his intestines that he, you know, would be able to live. And he did live and he did very well. And I thought it was the best operation


Daphna Yasova Barbeau, MD (she/her):

Hmm.


Gail Besner:

that I ever did. I thought nothing could be more exciting than this. But I can tell you that having done this for over 30 years now, if we could find something that would alleviate the need for pediatric surgeons to do this operation,


Daphna Yasova Barbeau, MD (she/her):

Mm.


Gail Besner:

I can freely speak for every pediatric surgeon in the country and in the world. who would be thrilled to the skies to never have to do this operation again. So I really love the motto of the NEC society to create a world without neck, because my vision is to create a department of surgery that never had to operate on


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

neck throughout the world. And that would really be the ultimate goal for me.


Ben Courchia MD:

Wow, that's awesome. That's such a nice sentiment, especially, as you said, coming from a surgeon. And I think what's even more interesting about your presentation today at the NEC symposium is that one of these therapeutic approaches that you are talking to us about involves probiotics. And so you are really getting into one of the most debated subjects right now in neonatology. And so can you tell us a little bit what your thoughts are on before we talk about lactobacillus rooteri Can you tell us a little bit what your thoughts are currently on probiotics and where and where we stand as a field in neonatology


Gail Besner:

So I think that one of the challenges with probiotic therapy is that nobody really knows what the best probiotic to use is, whether we should use a single probiotic strain or multiple strain probiotics. And it's really unclear as to what the dose and the dosing interval is. But one of the biggest challenges is that there's no FDA approved probiotic therapy that can be used for newborns in the neonatal intensive care unit. So as you know, you can go to the health food store or the drug store and buy hundreds of different types of probiotics with no problem at all. But what you see on the label is almost never what's actually in the bottle. They could be contaminated with unwanted bacterial strains, or there could be fungal contamination. And so you're never really sure what you're giving to the patient if you're using this medically. And when it comes to premature babies, they're the most vulnerable patients that we take care of throughout the whole entire hospital. And we really have to make sure that whatever it is that we're giving them, whatever therapy it ends up being that's gonna cure neck, has to be able to have an excellent chance of preventing babies from getting the disease without causing harm. So one of the problems is that you're giving live bacteria and so you could have a problem with the bacteria itself. And as I mentioned, there, there have been reports of contamination of the preparations. And although probiotics have been studied throughout our country and other countries in even randomized control trials, every single one of those trials delivered the probiotics in what we call their planktonic or free living state. Our strategy is quite different, we desire to administer probiotics in their biofilm state. So bacteria actually prefer to live in a community called a biofilm in which they self-produce a matrix that they surround themselves with that contains DNAs and RNAs and proteins that protect the bacteria from harm. Now, if you're a pathogenic bacteria, then doctors hate biofilms because it


Daphna Yasova Barbeau, MD (she/her):

Hmm.


Gail Besner:

stops us from treating bacterial


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

infections with antibiotics. And so patients can get very sick if they have a pathogenic bacteria that secretes a biofilm. But what we're talking about is inducing beneficial bacteria, probiotic bacteria to make a biofilm. And if we have a strategy that can do that, that it makes those beneficial bacteria more resistant to host defenses, more resistant to antibiotic therapy, more capable of competing with pathogenic bacteria, and more able to sustain the acidic environment of the stomach so that the probiotics can get through the stomach and make it to the intestines where they have to exert their beneficial effects.


Ben Courchia MD:

Mm-hmm.


Gail Besner:

So our strategy is really quite simple, although also quite novel. And what we do is we start with a beneficial bacteria known as Lactobacillus ruderi. And one of the advantages of that particular bacteria is that it can make antibacterial substances called reuterin or anti-inflammatory substances like histamine and infection and inflammation are two pathogenic processes that occur during necrotizing enterocolitis. So we start already with a beneficial bacteria that has good underlying properties. And then we incubate those bacteria with little tiny microspheres. And when those bacteria adhere to the surface of the microsphere, they start to produce biofilm. But the system is even much more powerful than that because we can load those microspheres with beneficial substances called prebiotic substances, and we can influence the bacteria to do what we want them to do. So we can influence the bacteria to make more antibacterial reuterine or more anti-inflammatory histamine or a lot more biofilm. And in our animal models of necrotizing enterocolitis, when we treat animals with this probiotic preparation in its biofilm state, we can almost eliminate the development of necrotizing enterocolitis. And when we compare Lactobacillus rudarii administration in its biofilm state compared to in its free-living planktonic state, the biofilm state is much more highly active.


Ben Courchia MD:

I would like to backtrack a little bit because I think many people, especially myself, I was not really familiar with this difference


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Ben Courchia MD:

between the planktonic state and the biofilm state. And I think that's already a point you've explained that's so fascinating where in its biofilm state where the bacteria is surrounded by matrix of DNA, proteins, lipids, and oligosaccharides, it really has a much better chance, as you've explained, to survive against the natural host defenses against bacteria in general. And so my question to you is when you're describing this new novel delivery system where the probiotic is being loaded onto these microspheres, you're basically telling us that you are creating the biofilm outside xx vivo. Basically, you are making the biofilm out in the lab and then introducing the bacteria as a biofilm into the organism. Is that correct?


Gail Besner:

That is correct, yes.


Daphna Yasova Barbeau, MD (she/her):

Was that the challenge of why it hasn't been used before? Or can you find the lactobacillus in the biofilm state?


Gail Besner:

I don't know that others have really investigated the powers of administering a beneficial bacteria in the biofilm state, because just as you weren't aware of it, probably most


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

other people aren't aware of it, but most importantly, there are no probiotics that have ever been delivered clinically in the biofilm state until ours. And I'm kind of gonna get to how that happened FDA approval, but although the probiotics have been delivered, Lactobacillus rudori has been studied in many clinical trials, it's always in the planktonic state, as has every other probiotic. Nobody has ever asked the FDA to administer any probiotic in its biofilm state. So thank you for your question, because it's a really important question that gets to the uniqueness and the innovation


Ben Courchia MD:

And


Gail Besner:

that we're using.


Ben Courchia MD:

how did this idea come about? How did you come up with this probiotic? Where did you read about it? How did you encounter this probiotic? I'm always interested in the inception stories of these research projects, so I


Gail Besner:

Yeah,


Ben Courchia MD:

have to


Gail Besner:

yeah,


Ben Courchia MD:

ask.


Gail Besner:

yeah. So I guess in a way we'll call it serendipity. But


Ben Courchia MD:

Ah.


Gail Besner:

about eight years ago now, I was giving a talk to the gastroenterologist in our GI department here at Nationwide Children's Hospital. And it was on necrotizing and orocholitis and potential therapies for necrotizing and orocholitis. Because before I really became invested in probiotics, I was very interested in growth factor therapy and stem cell therapy. So I was presenting that to the gastroenterologists. And the chief of gastroenterology at the end of the talk said to me, do you know Steve Goodman and Mike Bailey, other investigators that work in our, you know, nationwide children's hospital research programs? And I didn't. And he said to me, you need to meet with them right away because your work. is very important, you're gonna collaborate with them and this is gonna lead to something really important. So immediately, like, you know, within a day, I contacted these two individuals and really everything that I am presenting in my talk is a collaboration between three different separate, but synergistic laboratories at Nationwide Children's Hospital. My laboratory has a lot of expertise in necrotizing enterocolitis and in animal models of the disease. The laboratory of Dr. Stephen Goodman has tremendous expertise in biofilms and the laboratory of Dr. Michael Bailey in our research institute has tremendous experience in the microbiome of the gut. And so it's really been a tremendous collaboration and the three of us have much more than just an additive effect. It really is quite synergistic We, you know, early on, were very successful with NIH funding from the beginning of our collaboration and we really worked together as a wonderful team. So that's how the whole thing started. And I really believe that had I not taken the advice of the gastroenterology chief


Daphna Yasova Barbeau, MD (she/her):

Hmm.


Gail Besner:

and, you know, instituted this collaboration, I don't think we'd be anywhere near where we are now.


Ben Courchia MD:

Mm-hmm.


Gail Besner:

So basically, I collaborated with somebody that, you know, is one of the world's leaders in biofilms and in the microbiome. So that's how it all started.


Ben Courchia MD:

But it's a testament to also you taking on this chance at the end of a presentation where God knows how many people make comments and saying, hey, what you presented is great. You should probably do this. And some people say, you can just shrug it off and say, well, you know, I'm focusing on this. I'm not looking for collaborators, but you actually seek these people out. And so it's a kudos to you.


Gail Besner:

Yeah, well, I was really glad I did. It was a good advice. I'm glad I took that good advice.


Daphna Yasova Barbeau, MD (she/her):

I think


Ben Courchia MD:

And


Daphna Yasova Barbeau, MD (she/her):

it also speaks to how important collaboration is, right? And we talk about breaking down silos, quote unquote, but it really is about finding people who you may not have ever thought about collaborating with before. I do know, I say that also, that is one of the missions of the NEC Society is really to get people to collaborate, to meet each other, to go across disciplines, both during the conference and after the conference. that like just pushing forward with these really kind of landmark ideas.


Gail Besner:

Yeah, I think the point you're making is really, really so important. And we can do much better science as team science than trying to do it in individual silos. So, so thanks for pointing that out. And I fully wholeheartedly agree.


Ben Courchia MD:

And so the animal data for the use of Lactobacillus ruderi in animal models of neck and some of the data that you're presenting today is quite impressive.


Gail Besner:

Yes, thank you. So for many years we have used rodents as the species in which we did our neck research studies. And rodents are a good animal model because you can order many of them. And of course our models are in newborns because the disease occurs in newborns. It's a relatively cost effective model. However, when you look at the newborn prematurely delivered wrap pup, which is about the size of the distal half of your thumb, it really doesn't look like the premature babies that we take care of in the neonatal intensive care unit. However, prematurely delivered piglets are about the same size as the premature babies that we care for. They have many, many similarities in the intestinal tract as the babies that we take care of. And so one of the things that we thought was really important in transitioning our therapy to human beings was to see if we could replicate our very promising results that we got in rodents in a large animal model. And we chose to use the piglet, the prematurely delivered piglet, as our large animal model. And Before we did that, I want to just highlight something I think is really important in the field. Our goal as physicians taking care of babies with neck, of course, is to save them from dying from the disease.


Ben Courchia MD:

Mm-hmm.


Gail Besner:

But other experts in the field have really pointed out to us that it's not just the survival of the baby that's important. It's the neurodevelopment that the baby undergoes. if they're lucky enough to survive neck. And other investigators, neonatologist, surgeons, and others have identified the fact that babies that survive neck have neurodevelopmental delays. And so when they get old enough to test them, they have learning disabilities and other disabilities that we would really, really like to prevent so that not only can we save the life of the babies, but we can make them learn better. as


Daphna Yasova Barbeau, MD (she/her):

Thank


Gail Besner:

they get


Daphna Yasova Barbeau, MD (she/her):

you.


Gail Besner:

older and have less developmental impairments. And so in our rodent models of neck, when we did these studies in rats, we not only found that the probiotic preparation that we're talking about decreases mortality and intestinal injury in our animal model of neck, but in the survivors of neck. that we allowed to get older until we could test these rats at about two months of age, we found that they learned better, they had fewer learning disabilities, and there was less inflammation in their brains. And we were really like super excited about those results because not only perhaps can we save the lives of patients, but we can make them smarter as they grow and get older. So we thought that was just really, really fascinating and very important. Moving forward then, we did of course ask the FDA for approval to administer our probiotic preparation to human beings. In preparation for that, even before we filled out that FDA application, we developed a robust pig model of neck in our laboratory because it makes a whole lot of sense that before you transition to a human being, it would be good to have collaborating results. not only in rodents, but also in a large animal model. And so we were able to reproduce our findings in pigs, which we think is very, very important. And not only does our probiotic preparation protect the intestines from neck in pigs, but it also decreases inflammation in the brain of these piglets. So having all of that information, we did go to the FDA, a few... years back already and asked for permission to do what we call phase one clinical trials in patients. And the good news is that we did get permission, but the challenging part of it is that the permission was granted to do adult trials because basically no new drugs have really ever been tested in newborn human babies before they're tested in adults. But that's okay. We got the foot in the door. we got permission from the FDA to trial this in adults. And the adults that we chose to look at were adults with autism. And you might ask, why on earth would we look at autism? Well, just as I described to you that necrotizing enterocolitis is a disease of the intestines that also affects the brains of these babies, that happens because of something called the gut-brain axis. The concept is that whatever is happening in your intestine affects your brain. Whatever happens in your brain affects the intestines and there's cross talk between those two really important organs. Well autism is also a disease that highly affects the gut-brain axis and you and I think of autism as a brain disease. But the reality is that although that's true, Over 50% of patients with autism have significant gastrointestinal complaints. And so the gut brain axis is actively in play in autism. So we chose to make our phase one trial a trial of healthy human adults that happen to have autism. We signed up to 15 patients. And I have to say that people were knocking at the doors to try to register for the trial, because


Daphna Yasova Barbeau, MD (she/her):

and


Gail Besner:

I think that families of patients with autism are so desperate for a cure that it was very easy to find the enrollees. The study was completed and published several months ago. And what we found was that the drug that we're talking about, which is lactobacillus ruderite in its biofilm state, which is called SB121 in commercial terminology, we found that there were no negative consequences of giving it to human beings. Nobody had to withdraw from the study, but we found a really totally surprising finding. And that is that half of the patients had what we called a robust response to SB121. And when you think about phase one clinical trials, which are really very small trials that are only intended to look at safety of a drug, we didn't expect to see any efficacy. but there are questionnaires and other tests that one can do in patients with autism to grade their level of autism. And we found that half of the patients had surprisingly significant improvements in their autism scores. And that kind of really blew our minds because we just did not expect to see that, but it's really a lovely and a wonderful result. So. As we plan for a phase two trial in patients with autism, we can use those human data. And now we have robust pig data to show that SB121 protects pigs from necrotizing enterocytosis. We hope that we can use those data in our armamentarium to now get approval from the FDA to begin a phase one clinical trial in newborns. But the other incredible challenge with developing a drug from the bench to the bedside is the incredible cost that


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

companies have to put out in order to bring a drug from the bench to the bedside. And the most recent estimates I heard is that it costs $2 billion, billion with a B,


Ben Courchia MD:

Wow.


Daphna Yasova Barbeau, MD (she/her):

Hmm.


Gail Besner:

to bring a drug to clinical use. And necrotizing enterocolitis is a disease that affects perhaps... seven to 10,000 patients a year. Now, if you're the mother of that baby, then to you, that incidence is like 100%.


Ben Courchia MD:

Mm-hmm.


Gail Besner:

You know,


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

that is your baby, and your baby is at risk of harm from necrotizing enterocolitis. But if you're a drug company, and your intention of course is to make money, then


Daphna Yasova Barbeau, MD (she/her):

Hmm.


Gail Besner:

it's easier. to envision that a drug company is going to want to invest in a drug that will cure heart attacks or stroke or


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

cancer, which affects hundreds of millions of patients a year, rather than something that affects seven to 10,000 patients a year. So you have to find a company that's willing to toe the line and put in the effort and the money for a disease that is what we call an orphan disease. It


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Ben Courchia MD:

Yeah.


Gail Besner:

doesn't affect very many patients. But fortunately, Drs. Goodman and Bailey and I are the scientific co-founders of a company called Scioto Biosciences.


Daphna Yasova Barbeau, MD (she/her):

Mm.


Gail Besner:

And the company is invested in continuing to push this therapy forward so that we can not only treat patients with autism, but


Daphna Yasova Barbeau, MD (she/her):

Yeah.


Gail Besner:

hopefully treat patients with necrotizing enterocolitis as well. So that's my goal in the next year or two is to get FDA approval for patients with necrotizing enterocolitis so that we can hopefully repeat these studies in babies at risk of getting necrotizing enterocolitis.


Daphna Yasova Barbeau, MD (she/her):

I mean, that's, it's a remarkable journey. It sounds like what you guys have been able to do, especially by this kind of Trojan horse, one of the of the bacteria, but also in your research strategy, right into to see could this help other populations. And actually that brings me back to some of your other slides. You know, we talked you know, we're clinicians, Ben and I, and most of the time on the podcast, we're talking about the clinical findings and features of NEC. But your slides are really a good reminder of just the significant amount of inflammation and destruction that happens to the intestine. And so that was my question was, you know, are there other uses for this and other inflammatory GI problems? That's my first question. And my second is you do have a slide that shows us beautifully, this neck plus placebo and neck plus lactobacillus. Do you think this is something, you know, we talked a lot about prevention, so that's our goal, but could it be used as a rescue?


Gail Besner:

So all wonderful questions. So the first question was, what other diseases might this be able to treat? So since this is a neck symposium, and I am a surgeon that takes care of babies who are at high risk of getting neck, my number one priority is necrotizing and reclitis. But we have done other studies, particularly of a disease known as Clostridium difficile infection, or CDI. And Clostridium difficile, of course, is a pathogenic bacteria that results from an imbalance in your microbiome, as does necrotizing enterocolitis. There are microbiome or gut abnormalities in babies who are susceptible to getting necked. But although I mentioned that C. diff. affects 7,000 to 10,000 patients a year, Clostridium difficile colitis affects many, many more


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

than... many patients in excess of that. And it costs billions of dollars to the healthcare system every year. And it can result, it results from giving patients antibiotics and you can give patients as little as one dose of almost any antibiotic and they can get C. diff colitis. And it can be really, really debilitating. And we have some really lovely studies that show that our probiotic preparation can prevent animals from getting C. diff colitis. and also can rescue animals that already have C. diff colitis. So C. diff is a good example of another disease that can be benefited from this therapy. And I can think of others, you know, as well, for instance, inflammatory bowel disease that also is manifested by a lot of inflammation in your intestines. So if anybody listening wants to come and work


Daphna Yasova Barbeau, MD (she/her):

Hehehe


Gail Besner:

at my lab and look at those other diseases, please don't hesitate to contact me. So that was one question. And your other question is about rescue. So in our C. diff animal models, we can rescue or recover animals who already have C. diff before we institute therapy. In our next studies, we really have looked at prevention because it makes, I think that you could easily convince a neonatologist And these are the doctors that are taking care of these babies every day, 24-7, around the clock, 365 days a year. And I'm sure that every time a neonatologist loses a baby to neck, they are just really wanting a drug,


Daphna Yasova Barbeau, MD (she/her):

Yeah,


Gail Besner:

a therapy,


Daphna Yasova Barbeau, MD (she/her):

it's


Gail Besner:

anything that can prevent


Daphna Yasova Barbeau, MD (she/her):

devastating.


Gail Besner:

those babies


Daphna Yasova Barbeau, MD (she/her):

It's


Gail Besner:

from


Daphna Yasova Barbeau, MD (she/her):

devastating,


Gail Besner:

getting the disease,


Daphna Yasova Barbeau, MD (she/her):

yeah.


Gail Besner:

this devastating disease. So I think it would be a relatively easy cell to a neonatologist. to convince them to use a therapy if you told them that your therapy is safe, it's FDA approved, you're giving something that's highly purified, we know it's not contaminated, and even if you could reduce the incidence of neck, let's say by 75%, 50%, even 25%, a neonatologist would probably buy into that therapy. So... we've really concentrated on prophylaxis and not so much in rescue at this point. But in older studies where we looked at things like growth factors or stem cell therapy, they can be used as rescue therapy. So that's another avenue that we can look at as well. But I'm a firm believer that it's better to stop the baby from getting neck in the first place. than to try to treat them because once they're at death's door, there is no therapy that is going to


Ben Courchia MD:

Mm.


Gail Besner:

possibly bring back something that's dead or almost dead.


Ben Courchia MD:

I am fascinated by the whole story and your whole journey,


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Ben Courchia MD:

as Daphna mentioned, from this presentation that led you to collaborate with the current physicians you're collaborating with to the identification of this novel therapeutics, then to the animal data. But I am wondering, what is your feeling on the this journey that you have to go on where you're being asked to study a population that is not the population you originally intended to help, even though you're showing despite all these great outcomes in this population. Nonetheless, you are then faced with the economical challenges of continuing on this journey. And now you have to become an entrepreneur and


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Ben Courchia MD:

begin. How do you feel about all these detours that you are being forced to take, which sadly enough are exhausting time, which is a resource that a lot of patients and families are desperately needing. While you go through all these, I'm sorry, you have to go through all these hoops.


Gail Besner:

Yeah, it's a really challenging situation. You're absolutely right. So I believe that when it comes to science, a physician or PhD scientist is doing what they need to do in the laboratory. And I think it would be really challenging to expect a PhD scientist or an MD scientist to go out and be able to Garner the money that it costs to bring a drug to fruition clinically. And so I do believe that researchers and biopharmaceutical companies have to work together in order


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

to bring new therapies to the bedside. Sometimes the scientists can do it alone. Perhaps with devices it might be a little easier. But with drug development it's really challenging. And if as scientific co-founders, myself and my two collaborators didn't... work with a company to do this with our company is called Scioto Biosciences. I don't think we would have gotten anywhere near where we got now.


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

And I think the NIH even recognizes that because the NIH has grant money that is set aside particularly for academic institutions to collaborate with small biopharmaceutical companies in the early stages of drug development to try to bring novel therapies to the bedside. And we were fortunate. We got two or three of those grants. when we started out. And I think that really set us on our way to future success. But the re part of research means you're redoing it a lot and


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

it is challenging and it's not for the light of heart. And I really think that the key to successful research is persistence. It takes a little bit of luck and some serendipity and a lot of persistence letting anybody tell you that it can't be done. And if


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

you don't get your NIH grant the first time, reapply and reapply. And people say that you have to write 10 grants in order to get one funded. And maybe it might be even worse than that now,


Daphna Yasova Barbeau, MD (she/her):

Mm.


Gail Besner:

but I don't think we can ever give up


Ben Courchia MD:

Uh-huh.


Gail Besner:

because I'll tell you why. As a surgeon, as a pediatric surgeon, if I'm on call and I get called to the neonatal intensive care unit because there's a baby with necrotizing enterocleitis that needs surgery, I have to meet with those parents before the operation. And I have to tell those parents that there's only a 50% chance that their baby is gonna survive. And as a parent, I can't imagine hearing anything much worse than that your baby only has a 50% chance of even living within the next 24 hours.


Ben Courchia MD:

Mm-hmm.


Gail Besner:

And every time we lose a baby to neck that we've operated on, it takes a little bit more out of us.


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

And it just makes me even more inspired desperate almost, to try to help to find a cure for this, you know, awful disease. So we have to be persistent and almost obstinate, and we just can't ever give up because these babies need us. And it reminds me how important societies like the NEC society are. And the most fascinating thing to me about the NEC society is the following. As physicians, you and I go to lots of medical meetings. And almost all of the meetings that we go to, we're surrounded by our peers, which are other physicians. And every occasionally once in a while, an outsider, you know, a non-physician or a non-surgeon in my case is invited to the meeting. But the NEC society meeting is totally different. I'm completely fascinated by the fact that the society was founded by two mothers that...


Daphna Yasova Barbeau, MD (she/her):

That's me.


Gail Besner:

you know, were affected, their families were affected and devastated by necrotizing enteropitis. So that's the number one thing that I find the most exciting. But it's truly multidisciplinary and at these symposia are PhD scientists and MD scientists and clinicians taking care of these babies as neonatologists or as pediatric surgeons and nurses and therapists and all kinds of other personnel that are affected in having to take care of these babies day by day, not to mention the families that have been affected by the disease. And when you hear their stories, you can't help crying inside because you realize how truly devastating this disease has been to these families. And now we even have members that are survivors of NEC.


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

So who better to understand the disease than an actual survivor of the disease that has now gotten old enough to tell us what their experiences have been as a survivor of NET. So the multidisciplinary nature of these symposia is really exciting and... Quite frankly, it's eye-opening. And as physicians, we don't often get to go to meetings that are so multidisciplinary in nature, but that's really, really inspiring. And it inspires me for sure to continue researching, to continue the work that we're doing. And really another goal, important goal of all of us, is to train the next generation of physician scientists who are gonna do this research when we're not able to do it anymore.


Ben Courchia MD:

Mm-hmm.


Gail Besner:

because as you can see, necrotizing enteroclitis is a disease that was first described like in the 1960s.


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

So despite seven decades of research, we still are faced with this horrible disease to which there's still no known cure. So we have to plan for the future as well and train the next generation and inspire them to wanna do this research as much as we're doing this research.


Daphna Yasova Barbeau, MD (she/her):

I think you've painted such a kind of beautiful picture about what makes the NEC symposium so special. And I think you're highlighting some of the missions, right? They have a number of tracks this year, and you have your hands busy with the first two, the science and research and the clinical care and practices track. And I wonder, you've spoken a little bit about the difficulties in funding for this type of work specifically. And kind of what is our role as clinicians in advocating for change, especially to study like orphan diseases.


Gail Besner:

Yeah, I think that we have to be ambassadors. And as I said, I think that to generate the kind of funds that it takes these days to bring something novel to the bedside takes the collaboration with small biopharmaceutical companies who can then get larger biopharmaceutical, pharma companies involved in this technology. But it is challenging. And one thing that I've learned from the families of babies affected with neck that we have to keep in mind is that the first time most of these families have heard the words necrotizing enterocolitis was when their baby was diagnosed with the disease. And so what we need to do in our intensive care units, and the Neck Society is highly promoting this, is to get the families involved. Because the families are often with those babies 24 hours around the clock. at the bedside and they might be the first person to notice that something is just not quite right with my baby. The physicians are taking care of a lot of babies at once and the nurses have more than one patient at once. By the time it becomes clinically obvious to the clinician, the disease has already started and sometimes, as I said, it can be really rampant and have a rapid downhill course. But we should teach the parents what to look for. And when those parents say, you know, something's not quite right with my baby today, we have to listen to that because they may be the first to notice. And perhaps if we notice it early, we can change something in what we're doing to try to alleviate the disease before it really undergoes that rapid downhill spiral. We may not be able to, but at least there's a chance. And the other really important contribution that needs to be made to the field is to discover a biomarker for necrotizing enterochitis. In


Ben Courchia MD:

Mm-hmm.


Gail Besner:

other words, before the baby is really distended and has an X-ray that shows X-ray findings of necrotizing enterochitis, if there was a urine test or a stool test or a, um, a blood test that could diagnose necrotizing enterochitis in advance, perhaps several days in advance of the patient becoming clinically ill, that would be a game changer. because then the FDA would be very happy. Because instead of saying to the FDA that we have to treat 100 babies instead of saving seven of them from getting neck, we can say to the FDA, we have a novel therapy and it's these seven to 10 babies that we know are at highest risk of getting the disease because we have a blood test that shows that.


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm. Mm.


Gail Besner:

And then the FDA will be much more amenable to novel therapeutics.


Ben Courchia MD:

Gail, we're coming to the end of our discussion, and I had one more question for you, and it's really related to the fact that I'm fascinated by your duality and your dedication to clinical care and your excellence in basic science research, because studying animal models in the lab and taking the time to do all these things is quite fascinating. What is your advice for people who are striving to fill your shoes and become both... great clinician and expert researchers, how do we get to reach this balance in those two spheres?


Gail Besner:

Yeah, thanks for asking because I have people that come to my office, not infrequently. They may be physicians, they may be PhDs, but if they're physicians, I can tell you that if they're interested in having a clinical practice and doing research, someone has told them that it can't be done.


Ben Courchia MD:

That's right.


Gail Besner:

And that really upsets me because I believe that it can be done. And the advantage of being an MD who does research is that we're kind of in the nitty gritty of it. And we're there taking care of those patients and struggling with problems at the bedside that we can conceive of might have a therapy that we could find in the laboratory. So in terms of significance, the clinician scientist really gets the significance of what diseases really need to have intensive research dedicated towards those diseases. Now the downside or the advantage for the PhD is that they have a lot more time. They don't have to deal with all the clinical stuff that we have to deal with. And so they have an advantage in terms of time and training. They're extraordinarily well-trained. I can tell you, cause my husband is a PhD, so I don't mind talking about PhD scientists, but don't discount the power of the physician scientist. or the surgeon scientist either,


Daphna Yasova Barbeau, MD (she/her):

Mm-hmm.


Gail Besner:

because we really get the clinical significance of what we're doing. So to answer your question, I think that the number one thing that I look at when that person sits down at my office table is do they have the passion and do they have the willpower to make it work? Because it isn't easy and it's like wearing two hats. It's almost like being schizophrenic. You have your doctor hat and you have your scientist hat. and you have to, you know, kind of find the time to be able to do it all. But if you have a burning desire within you to do it, then don't let anybody tell you that it cannot be done because I believe that it can be done. And I'm not minimizing the, um, uh, the challenges or the difficulties that one can encounter. I mean, I've been doing this research for 30 years, but


Ben Courchia MD:

Mm-hmm.


Gail Besner:

there are physician scientists have that have been doing research for 40 or 50 years. and just coming to incredible findings. We have one of them in our research institute now, who after 50 years has made a discovery that's just mind blowing.


Ben Courchia MD:

Mm-hmm.


Gail Besner:

So don't ever give up and don't ever let anybody tell you that it can't be done because it can.


Daphna Yasova Barbeau, MD (she/her):

Hmm.


Ben Courchia MD:

I love that. I think this is a great touch for us to end on. Gail, thank you so much for taking the time to sit down with us today. We hope to run into you again during the NEC symposium and we will link a lot of the papers that you quoted in your presentation on the episode page. So for people who are interested in finding out more about Lacto-Vesillas-Ruderi and some of the papers that have already been published on the subject. So We'll link all that stuff in the episode page. Thank you. Thank you so much for taking the time to be with us today.


Gail Besner:

Right, thank you for your time as well. Really appreciate it.


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