* Surgical outcomes of NEC and the role length of intestine plays in those outcomes
* Her serendipitous discovery, and continuous research, of a growth factor (HB-EGF) that can play a role in protecting babies from NEC
* Her current research of stem cells and tissue engineered intestine in prevention and treatment of NEC
* The importance, and inherent challenges, of funding research in NEC.
Copyright © 2015 The Morgan Leary Vaughan Fund, Inc. This episode was produced in part by the TeacherCast Educational Broadcasting Network.
STEPHANIE VAUGHAN, HOST:
Welcome to Speaking of NEC: Necrotizing Enterocolitis—a free, audio podcast series about Necrotizing Enterocolitis or NEC.
Produced by The Morgan Leary Vaughan Fund, and funded by The Petit Family Foundation, Speaking of NEC is a series of one-on-one conversations with relevant NEC experts—neonatologists, clinicians and researchers—that highlights current prevention, diagnosis, and treatment strategies for NEC, and the search for a cure.
For more information about this podcast series or The Morgan Leary Vaughan Fund, visit our website at www.morgansfund.org
Hello, my name is Stephanie Vaughan. Welcome to the show. I’m the Co-founder and President of The Morgan Leary Vaughan Fund.
One of the goals of this series is to shine a light on the individuals who are actively pursuing a cure for NEC. One of them being today’s guest: Dr. Gail Besner, chief of Pediatric Surgery at Nationwide Children’s Hospital in Columbus, Ohio.
Dr. Besner may truly be on the cusp of curing NEC. Her breakthrough discovery, and 20 plus years of continuous research, has led her to an FDA approval for a Phase I Clinical Trial of a growth factor (HB-EGF) that can play a role in protecting babies from NEC.
The roadblock to starting that trial: funding.
Dr. Besner will share with me today her experience with NEC as both a surgeon and scientist. She will also discuss the critical need for funding in NEC research. The estimated cost of a Phase I Clinical Trial for HB-EGF is $1 million.
That, however, is only a fraction of what it would cost for a biotechnology or pharmaceutical company to bring a new drug to market, which is currently estimated at $2 billion. In actual numbers, the estimated cost of Dr. Besner’s trial is one twentieth of one percent (0.05%) that of bringing a new drug to market. Yet, the potential ripple effect of a successful trial is huge.
Imagine effectively treating and preventing any number of intestinal diseases or injuries. The least of which would be NEC. Then, imagine the positive impact on those patients and their families. The least of which would be the smallest and most fragile babies, those at the greatest risk of developing NEC.
With that in mind, let me introduce my guest today.
This is Dr. Gail Besner from Nationwide Children’s Hospital and I’m so glad that you could join me today. How are you?
DR. GAIL BESNER, GUEST: I’m wonderful. Thank you so much, Stephanie—it’s a real honor to be able to speak to you and to some of the other family members and parents and other interested parties for patients that have Necrotizing Enterocolitis.
STEPHANIE: Thank you. So I guess tell me a little bit about your work with Necrotizing Enterocolitis in the NICU. You know, doctor to patient, doctor to parent—what’s your experience with NEC?
DR. BESNER: Absolutely—so if it’s okay with you, I just want to go back and give you a little bit of historical perspective.
DR. BESNER: And I’ve been a pediatric surgeon practicing actively at Nationwide Children’s Hospital since 1991, and the first operation that I ever did for Necrotizing Enterocolitis was during my pediatric surgery training, and that was in 1989. And I operated on what was then considered a very small baby, which was a 900 gram (1 pound 15.75 ounces) baby that we did a bowel resection on for Necrotizing Enterocolitis, and he actually lived. And I thought it was one of the most wonderful, spectacular operations that I’ve ever done, but unfortunately, I’ve really learned to not like this operation, and if I could possibly put myself and other pediatric surgeons out of business in that respect and never have to do this operation again, I think that I can speak for myself and all of the other surgeons that we would be really, really happy and satisfied if we never had to operate on these babies again. So the thing you have to keep in mind is that Necrotizing Enterocolitis is a disease that was first described in the 1960s. So think about how many decades that was ago, and the sad thing about it is that, although we know a lot more about the disease now than we did in the 1960s, the mortality of this disease, although it’s gotten a little bit better, is still really unacceptable in our minds.
DR. BESNER: And if I take a call, for example, tomorrow, and I unfortunately end up having to operate on a baby with NEC, I have to tell the parents that there’s only a 50% chance that the baby might survive, which means, tragically, that there’s a 50% chance that the baby won’t survive, and that’s really heartbreaking to me, because I can only imagine, as a parent, what that kind of information means to them. And I would do anything to really change those numbers. Despite all of the sophisticated medical instruments and techniques and methodologies that we have now, both on the medical standpoint and on the surgery standpoint, the mortality and the morbidity, the complications associated with the disease really haven’t changed. So as physicians, we’re really devastated by that fact.
STEPHANIE: As parents, we are too.
DR. BESNER: The bottom line—the bottom line is that if the baby is very small and very fragile and ends up having to have surge for NEC, the mortality is still as high as 50%.
STEPHANIE: Mm-hmm. So when you’re talking to parents about NEC, with a successful surgery, what are you telling them that they’re looking for in outcomes for that?
DR. BESNER: Sure—so if we operate on a baby with NEC, I think that the most risky, problematic period is the following 24 to 48 hours. If the baby survives during that timeframe, then there’s a much better chance that they’ll end up surviving from the operation in general, but how they’re going to do in the long run really is dependent upon how much intestine we have to remove in the operating room. If we only have to remove a little bit of intestine, or maybe a moderate length of intestine, the baby could end up doing quite well. Sometimes, however, we have to remove a very large length of intestine, and those are the babies that end up having something called Short Gut Syndrome, which you’re probably familiar with, and those are the babies that are really going to be a challenge to us. They’re going to be on total parenteral nutrition, which is intravenous, high-calorie feeds, for a very long time. And hopefully, slowly over the months and over the years, we can get them off TPN, but some babies will never, ever have enough intestines to be able to survive, so the answer—or I shouldn’t say that—I should say they’ll never have enough intestines to be able to eat and sustain themselves by nourishing themselves with a diet by mouth. So the answer to your question about what the parents can expect completely depends on what the surgeon is forced to do in the operating room.
DR. BESNER: And again, if we only have to remove a relatively small amount of intestine, the baby’s going to do very well. And if we have to remove a lot of intestine, those are the babies that are going to be the greatest challenge for us.
STEPHANIE: So I’m curious, for when you’re saying a small amount versus a larger amount. My son had approximately eight inches (20 centimeters) of intestine, and from what I understand, that’s about 20% of his intestine was removed. And he’s doing very well. He doesn’t have any residual at four years old. So I’m curious where the doctor’s standpoint is in metrics or inches.
DR. BESNER: Yeah, absolutely.
STEPHANIE: Between a good situation and a not so good situation.
DR. BESNER: Sure, sure—so there’s one good thing about being a premature baby, aside from the fact that there are many big challenges about being a premature baby—for example, you’re subject to getting Necrotizing Enterocolitis and other problems—the one good thing about being premature is that if the surgeon has to remove your intestines, the intestines are still growing at that stage of development, and so the baby still has a chance to regain some of the length of the bowel. So let’s say a baby loses 75% of their intestines. That’s bad, but it’s nowhere near as bad as if an adult loses that length of intestine, because an adult has completed all of the growth that their intestines are ever going to have. So the one thing the baby has in their favor is that they still have the opportunity to grow a little bit more length of intestine. But in answer to your question, if we estimate that a newborn baby has approximately 200 centimeters (78.74 inches) of intestine, they have to be left with at least 40 centimeters (15.75 inches) in order to be able to nourish themselves and get off TPN. These aren’t exact numbers, but they’re relatively—
DR. BESNER: reliable numbers. But we should never say never, because I had a spectacular case of a baby—a beautiful baby boy who was a twin. One twin was absolutely fine, never got Necrotizing Enterocolitis never needed surgery. The other twin developed severe Necrotizing Enterocolitis. I had to operate on him and remove a massive amount of small bowel, and he was only left with 20 centimeters (7.87 inches) of small bowel, so he really had ultra-short length of intestine, and of course, I had to tell the parents, you know this is a very severe situation. If he lives and we’re lucky enough for him to survive, he may never be able to eat enough to get off of TPN, and he was a miracle baby. Within six months, he was off TPN, he became very well nourished, and the most striking thing—I see him every year, and his parents send me a lovely holiday gift every year—but the most striking thing I remember about him was that, throughout his life and his development, he has been bigger in size and in weight and in height than his twin brother who never had surgery. So he is an unusual, spectacular case of a really great success story of a baby that had extremely short length of intestine and yet went on to not only survive, but to excel and to do beautifully. He’s a baseball player—he’s just doing great. So we should never say never, and we always have to try our hardest, because you just never know how any one individual baby is going to react.
STEPHANIE: That’s wonderful—yeah, my son Morgan that had Necrotizing Enterocolitis actually outpaced his brother in weight and height at about eight months old, and we were shocked.
BESNER: That is just wonderful. So you know exactly what I’m talking about.
DR. BESNER: Yes, yes—so now we’ve been talking about length of intestine and what that means for the babies. So talk to me a little bit about your research in particular, because I know this is—this is really where your research is—is going.
DR. BESNER: Yes, thank you for asking. So I have really dedicated the research part of my career to the disease of Necrotizing Enterocolitis, because it’s such a devastating disease, and it affects the most fragile babies that we have in the hospital, and as I said, we haven’t made all that much progress in terms of improving survival over the years. So we’re still incredibly challenged by this disease, and it warrants a lot more work until we really can say that we’ve made a difference. So in the late 1980s, I did a pediatric surgical research fellowship, and I accidentally—or serendipitously, as we like to refer to it, discovered a growth factor that I believe can play a role in protecting babies from Necrotizing Enterocolitis. And a growth factor is simply a protein, it’s naturally occurring, it’s made by our own cells in the body, and it’s a protein that stimulates cells to grow and to move, and the growth and movement of cells is particularly important in the process of wound healing. And if you think about the intestines, a disease like Necrotizing Enterocolitis starts out as a wound, and if we could enhance the body’s own ability to heal the wound and to strengthen and mature the intestines, then perhaps we could save babies from developing Necrotizing Enterocolitis in the first place, or we could take babies with very early stages of the disease and hopefully stop them from progressing to the more severe stages of the disease that requires surgery. So we, over the years, have conducted numerous experiments, both at the molecular biology level and the cell biology level and other, more complex, experimentation methods, that lead us to believe that we can treat Necrotizing Enterocolitis by simply adding this growth factor to the feeds that an individual receives. And in the more recent years, we’ve become very, very interested in the ability of stem cells to protect the intestines from injury, so stem cells are cells that have the ability to differentiate or to change into many, many different cell types in the body, and intestinal stem cells, which reside in the lining of everybody’s intestines, can differentiate into all of the other cells that comprise the intestine. So we believe that if we can protect those very important intestinal stem cells from injury, we might be able, again, to treat or to prevent Necrotizing Enterocolitis. And in fact, we’ve undergone and carried out numerous experiments showing that we can harvest and purify stem cells, deliver them in a model of Necrotizing Enterocolitis, and protect the intestines from developing the disease. And very interestingly, if we give HB-EGF, this growth factor that I’ve been working on, if we give it in conjunction—at the same time as the stem cell therapy, we can even better protect the intestines from the disease of Necrotizing Enterocolitis. So we’re very, very interested in utilizing these types of methodologies to protect babies from getting Necrotizing Enterocolitis in the future. And the most recent thing that we’re doing in the lab is an extremely exciting project, and it refers to those babies that I told you undergo surgery, but they’re left with such a small length of intestine that they just can never be able to nourish themselves, and they’re requiring this total parenteral nutrition for the rest of their lives. And one of the ways that we would like to treat that is with a methodology known as tissue engineering, and what we would like to do is to create tissue-engineered intestine. So the baby does not have enough length of their own intestines, but we’re trying very desperately to be able to start, with a tiny little biopsy of the patient’s own intestine, to grow that tissue in the laboratory, and then to use those cells to produce tissue-engineered intestine by taking those cells, seeding them onto a scaffold or a backbone material that will eventually disappear and be degraded by the body itself, but during that process, it will turn into engineered intestine that can replace the baby’s lost intestine. So that’s a very ambitious project that we’re undergoing, but it’s a project that we feel very passionate about, and we have several people in my laboratory working on the tissue-engineered intestine project, and several people in the laboratory working on the Necrotizing Enterocolitis project. So both of them are very near and dear to our hearts, and I do believe that both of those projects are extremely important in our ability to treat those tiny, fragile little babies in the nursery in the hopes of protecting them from Necrotizing Enterocolitis in the future.
STEPHANIE: And it sounds like those applications really could be applicable to many patients with a wide variety of intestinal issues, including the premature babies, but even up through adulthood and other people that have had to have similar surgeries, I assume.
DR. BESNER: Yes, that’s a really, really good point, and I’m very glad you brought it up. So the methodologies that we’re developing in the laboratory would be very helpful for premature babies, but they would be applicable to many different patient populations with injury to the intestines that originated from many different types of diseases. So these types of methodologies could be applicable to newborn babies, to children, to teenagers, and to adults, and not just patients that suffer from Necrotizing Enterocolitis, but patients that suffer from injury to the intestines of many different sources.
STEPHANIE: That’s very exciting.
DR. BESNER: Thank you, yes. We agree. We hope so. We hope it continues to go in the right direction.
STEPHANIE: Right—so talk to me a little bit about moving towards clinical trials. Now I know you’ve said that you are working in the labs and have models, and I’ve read some of your articles and some of your research that has a fairly ambitious goal of five—five to eight years to possibly be in clinical trials. What does that mean for these babies with NEC?
DR. BESNER: So one of the things that we’ve found really challenging, and one of the things that I think challenges research on babies in general, is the fact that, whenever you discover something new in the laboratory and want to translate it to the actual care of a patient at the bedside, of course we have to get approval from the Food and Drug Administration. And we all recognize and we all agree that that is an extraordinarily important process, and one that protects patients from harm in all different areas of medicine. But in order to get something approved in babies, the drug or the methodology typically has to be approved first in adults, and studies like that are rather costly. And interestingly, we actually have the ability to give HB-EGF to humans at this time. We have approval from the Food and Drug Administration, but we’ve never done it yet, and the reason we haven’t done it is because the FDA wants a complete, full adult trial to look at the safety of this drug before we even attempt or think about giving it to babies, and doing this trial in adults is very costly. So until we can generate enough funds to actually do this type of what we call a Phase I Clinical Trial in adults, we’re really not going to be able to push forward and do anything in babies. So we’re kind of in a little bit of a holding pattern in the hopes that we can find some source of funding, and we’re talking—we’re not talking about $100 million dollars. We’re talking probably about a million dollar trial in healthy adults to try to just see if they can tolerate administration of this growth factor. But that’s not the most important part. The most important thing is that whenever you develop a new technology, it’s challenging, number one, to bring it to the clinic, but it’s not impossible. But it’s particularly challenging in newborn babies, and especially if you’re talking about trying to protect babies from Necrotizing Enterocolitis, you’re talking about something that affects maybe a few thousand babies every year. Compare that, on the other hand, to something like heart attacks, which affect millions and millions of adults every year, and if you’re a drug company trying to develop a new drug, it’s now estimated that it costs not one, but two billion dollars—that’s billion, not million—two billion dollars to bring a new drug to the market. So if you’re a drug company, and you’re developing a drug, it’s probably more likely that you’re going to want to promote and develop a drug to treat or prevent a patient from getting a heart attack than to prevent a baby from getting Necrotizing Enterocolitis, just from the financial standpoint. So that’s yet another challenge that we have to overcome. We have to be able to care for those fragile, tiny babies in a disease that doesn’t affect all that many of them, but on the other hand, if you’re the mother of that particular one baby who gets Necrotizing Enterocolitis, then to you, it’s the most important patient in the whole entire world. So we have to figure out a way to get companies and biotechnology firms interested in the disease like Necrotizing Enterocolitis, which is called an orphan disease—it’s a disease that doesn’t affect hundreds of thousands or millions of patients every year. It affects only a few thousand patients every year, but nevertheless, it’s incredibly important if you’re caring for those patients or if you’re the family member of those patients.
STEPHANIE: Thank you, I think that’s a great way to put this disease and the need for funds for research into perspective. And as the mom of a surgical NEC survivor, he and his brother were the most important patients to us and for families of children at risk for NEC or that are suffering from NEC, you’re right, they are the most important patients. And that’s what we’re trying to do with this series and also with our organization, is to bring attention to this disease, and hopefully help the doctors and the clinicians and the researchers get that funding and advance the research that you’re doing now.
DR. BESNER: Yes, thank you. And the other thing I think that it’s important for the public to know is that the main source of funding for researchers in the United States is the National Institutes of Health, and I’ve been funded from the NIH for the last 20 years continuously, which is wonderful, but the NIH does not fund certain types of research. For example, they’re never going to fund a Phase I Clinical Trial of giving this growth factor to healthy human adults. They just don’t fund that kind of research. And so we’re really dependent on either a biotechnology company or a drug company funding this kind of research, or more importantly, philanthropy. If we had philanthropic support, that would really, I think, push the field forward. So these are the kinds of things that we’re struggling with in the laboratory these days. And in case your listeners are interested, the other problem with research right now is that funding from the NIH, which is the American government’s most prominent source of funding, is at an all-time low. So I’m very grateful to have continued NIH funding, but many, many investigators have lost their funding or had decreased funding, and new investigators are struggling to even get funding. So the funding situation in America right now is very, very concerning to us.
STEPHANIE: Thank you, I think these are, like I said, great perspectives to share with people. Our family lived with this disease firsthand, and we know the miracles that the surgeons and doctors perform every day, and we appreciate it, and this is our way of promoting you as the doctor and researcher and to get the word out about NEC and raise awareness and advance research in this field. So I really appreciate you taking the time to talk to me today, and if there’s anything else that you’d like to add, feel free.
DR. BESNER: Well, I appreciate that so much, and I think that if anybody out there listening is interested in funding this kind of research, all it would take is a walk through the neonatal intensive care unit. And you can do that in any local children’s hospital that happens to be near you, and if you would walk through the neonatal intensive care unit, what you would see are little premature babies that are the size of your hand. So look down at your own hand, and if you’ve ever had children, then you know they come out as big, huge, bouncing, healthy babies—think about a baby coming out the size of your hand. They’re so fragile that their skin is practically see-through. They can’t hardly breathe, and if they get Necrotizing Enterocolitis, there’s a 50% chance of them dying. So look at your hand and think about that, and if you have it in your heart to try to help these babies, then think about funding research for Necrotizing Enterocolitis. There are many wonderful investigators throughout the United States that are passionate about this disease, and we could really use the help. So anybody who wants a tour of the neonatal intensive care unit, if you’re anywhere near Columbus, Ohio, I’ll be glad do it, but go to your local hospital and ask for a tour, and they’ll be glad to show you what these babies look like.
STEPHANIE: Thank you. Thank you so much for joining us today, Dr. Besner. And I hope to talk to you soon.
DR. BESNER: Thank you so much. It was a real pleasure, Stephanie. I really appreciate it.
STEPHANIE: For more information about Dr. Besner and her research in NEC at the Center for Perinatal Research in The Research Institute at Nationwide Children’s Hospital, visit www.nationwidechildrens.org. A direct link can also be found in this episode’s show notes: http://www.nationwidechildrens.org/center-for-perinatal-research.
In closing, I’d like to share a few thoughts about today’s conversation with Dr. Besner.
My son Morgan had an atypical case of NEC. I pumped. He and his brother Shaymus received my breastmilk, trophic feeds, and probiotics. Yet, at four days old, Morgan developed NEC after only two attempted feedings. Shaymus never developed NEC.
Morgan’s case shows that although there are many preventative strategies for NEC, currently none are 100% effective. And as Dr. Besner pointed out, “the bottom line is that if the baby is very small and very fragile, and ends up having to have surgery for NEC, the mortality is still as high as 50%.”
As the Mommy of a surgical NEC survivor, I believe that a cure for NEC, once found, will have a far reaching impact on Gastroenterology (the digestive system and its disorders).
Show your support for our smallest and most fragile babies, those who have the greatest risk for developing NEC. Show your support for continued research in NEC. And join our effort to raise awareness about, and funds for research in NEC by making a donation to Morgan’s Fund at www.morgansfund.org.
If you’ve had a personal experience with NEC and would like to share your story, or have a question or topic that you’d like to hear addressed on our show, e-mail us at email@example.com. We’d love to hear from you!
You can make a donation directly to Dr. Besner’s research in NEC at the Center for Perinatal Research in The Research Institute at Nationwide Children’s Hospital by visiting http://www.nationwidechildrens.org/giving
Note: Donors should write Besner NEC Research in the comments section of the online form.
Or, you can mail a check to:
Nationwide Children’s Hospital Foundation
PO Box 16810
Columbus, OH 43216-6810
Note: Donors should include a note or write Besner NEC Research on the memo line of their check.
Copyright © 2015 The Morgan Leary Vaughan Fund, Inc.
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