* The two surgical options, laparotomy and perinatal drainage, commonly used to treat NEC
* His current research of biomarkers (indicators) that can predict the development or course of NEC leading to surgery
* Genetic predisposition and environmental risk factors of NEC
* Not-for-profit and industry funding for biomedical research, and some of the inherent challenges specific to NEC
* The complementary roles of clinical/translational research and basic science research in the prevention and treatment of 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 Episode 3 of Speaking of NEC—a free, audio podcast series about Necrotizing Enterocolitis.
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 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.
I’m privileged to have as my guest today Dr. Larry Moss, Surgeon-in-Chief at Nationwide Children’s Hospital in Columbus, Ohio.
Prior to his appointment at Nationwide Children’s Hospital, Dr. Moss was the Surgeon-in-Chief at Yale New Haven Children’s Hospital. It was during that time that Morgan underwent his two surgeries at Yale, and spent 105 days in their Newborn Special Care Unit. Dr. Robert Touloukian, who has since retired, was Morgan’s surgeon. However, Dr. Moss was one of the investigators in the study in which we allowed Morgan to participate while at Yale.
I’d like to share something that I wrote (and that lives on our website) about Morgan’s first foray into academia, which occurred the morning after his first surgery:
After a couple hours of sleep, I returned to Yale with my mother to visit Morgan. During our visit, I was asked if we would allow Morgan to participate in a study being conducted at Yale on NEC. The purpose of the specific study was to attempt to identify biomarkers in babies that were suspected of, or diagnosed with, NEC.
Jeff and I were in immediate agreement to allow Morgan’s participation in the study. The decision was easy for us. It was made in response to the question in the forefront of both of our minds: if one, then the other? If Morgan had developed NEC, would Shaymus?
It was the critical question that no one could answer for us.
We were told that there is no definitive reason why one baby develops NEC and not the other; nor is there is a definitive way to know which baby might be predisposed to developing NEC.
By allowing Morgan’s participation in the study, we felt that we might help answer that critical question for some other family in the future. Or better yet, prevent that question from having to be asked.
As a study participant, Morgan would need to donate urine and blood samples. Each of which would be gathered by non-invasive means. The one-time urine sample would be taken from one of Morgan’s soiled diapers. The one-time blood sample would be taken from a routine blood draw for purposes required by his treatment.
During that initial conversation with the study coordinator, I began to learn how little is actually known about NEC. Also during that conversation, the seed was planted in my mind for what would become The Morgan Leary Vaughan Fund.
Perhaps luck, or grace, has brought things full circle. With that in mind, let me introduce my guest today.
This is Dr. Larry Moss from Nationwide Children’s Hospital and I’m so glad that you could join me today. How are you?
DR. R. LAWRENCE MOSS, GUEST: I’m doing great, how are you, Stephanie?
STEPHANIE: Good. So, I’d like to talk to you about your work with Necrotizing Enterocolitis.
DR. MOSS: Sure.
STEPHANIE: And then into a little bit about your research, which I know a little bit about because I believe that our son Morgan was actually in one of your studies that was being held at Yale when he was there in 2010 and 11.
DR. MOSS: We had a couple of studies going on at that time, so I think you’re right.
STEPHANIE: So, I guess, let me ask from the surgical perspective your work with NEC.
DR. MOSS: Well, the history goes back a long way for me, I mean it started…my interest started early in my career, when I would sit there in the middle of the night with families who had an unfortunate baby with NEC who needed an emergency operation. And I’d have to tell them that we had several options and we honestly didn’t know which operation was best but…so we were just going to sort of make our best judgment and move forward. That was very frustrating—that’s what motivated me to become interested in researching these questions so we could try to do better.
STEPHANIE: Okay, just for edification of parents and families that might be listening. Can you talk a little bit about any difference between the two typical procedures for NEC?
DR. MOSS: Well, you could break them into two broad categories. The first is called a laparotomy, which is just a surgical word that means opening the abdomen. And it’s consistent with the traditional way we treat ruptured or dead intestine in a person of any age, which is to make a large incision, bring all of the intestine out of the abdomen, remove any thing that is dead or has a hole in it, and then bring out what we call stomas which is the free, open end of the intestine out through the abdominal wall because you can’t safely sew them back together. So, that’s one option. Another surgical option which is radically different is something called peritoneal drainage, which involves just making a tiny, little quarter-inch incision in the lower right side of the abdomen, and putting a little rubber drain into abdominal cavity, draining out the bad stuff and continuing the antibiotics and hoping out for the best.
STEPHANIE: And how do you, sort of, make a determination…I’m sure it’s a case by case, but in a general way—how do you make the determination between moving to surgery or doing the second procedure?
DR. MOSS: So, let me just take a little bit of a detour. So, the first determination is whether a baby needs an operation at all.
DR. MOSS: And that determination is made based on whether there is evidence that the intestine is either dead, part of the intestine is dead, or ruptured, has a hole in it, or perforation in it. If neither of those are the case, then NEC is best treated with antibiotics and intestinal rest. So, once we’ve made the decision to do the operation, the two choices I gave you are the surgical options or the two different types of operations you can do, and when I trained in this field, and for the early part of my career, there was a huge amount of debate of which of these procedures was better and which was better in certain circumstances, and there’s a gigantic literature arguing one way or the other, all of which was inconclusive at the time I was faced with having to decide what to do with my patients.
STEPHANIE: Okay…So, it was just, sort of, case by case, based on what you’re seeing at the time.
DR. MOSS: Well, it’s like a lot things in surgery. It was very colloquially based, so people tended to either do what they were trained to do, and they’d done in their personal experience, or there was also a lot of geographic variations. So, there were some places in the country where if your baby was sick in that city, you were highly-likely to get a laparotomy and other places where if your baby was sick in a different city, you’d be highly-likely to get a drain. And this isn’t because everyone was trying to do what they thought was best, it’s because we didn’t really have any hard evidence to know which was better.
STEPHANIE: Mm-hmm, and that was one of the areas that you started to research.
DR. MOSS: So, that’s one of the initial ways I got interested and started research was just to design and do what’s called a clinical trial, or an actual experimental study where we had a group of babies who met specific criteria and after agreement of the families they were actually randomly assigned to one of the operations or another and when we completed the study we could look back at the data and draw some conclusions.
STEPHANIE: And, what were those conclusions?
DR. MOSS: So we did that, and we had 13 participating centers around the country, so a lot of individuals put a lot of effort into doing this. And, much to our surprise, what it turns out is that the type of operation that’s done for the disease didn’t matter at all. And the outcome for these babies was the same, regardless of what operation they had, which, sort of, erased 20 or 30 years of debate about which one was better, or at least in some people’s minds. And, so that refocused our efforts, I’m sorry, that refocused our efforts into trying to determine, trying to think upstream and look more critically at well what babies are at risk for NEC, and more importantly if a baby gets NEC, what are risk factors for developing a perforation and needing surgery so that we could intervene earlier.
STEPHANIE: Umm hmm…So, can you explain, I guess, what your research studies were in that area?
DR. MOSS: So, where we’ve evolved now is to try to look for indicators called “biomarkers”; and biomarkers are substances in the bloodstream, or in any body fluid of a patient, that reliably predict a certain status or a certain disease. So, we started out looking in the bloodstream and we’ve evolved to looking in urine as well, using a technique called proteomics, and the way that works…Stop me if this is more detailed than you want…but the way that works is we’re able to take a just a tiny drop of blood, and using microtechniques, look at literally tens of thousands of proteins in that blood and quantify them, or figure out how much of each one is present, and by doing that and using some pretty sophisticated statistics, we’re able to hone down into 3, 4, 5 or 10 proteins that seem to be relevant and predictive of either the development of NEC, or more importantly, the course of NEC leading to surgery and allow us to identify these babies earlier.
STEPHANIE: That’s great. I think that’s actually the, probably one of the studies that Morgan, was actually participated in.
DR. MOSS: You’re correct. That’s exactly the one he was in.
STEPHANIE: Right, and our thought was, you know, he has a twin brother and, what better way for us to help other families than to, you know, have him participate and, you know, be part of something that’s going to predict who’s more at risk.
DR. MOSS: And that’s a really good observation, Stephanie, is what happens in twins. You’d think, well if this is just a genetically predisposed disease—if one twin gets it, the other twin should get it. And as it turns out, there’s a slightly higher incident in the second twin when they’re genetically identical, but nowhere near a 100%. And so, we believe that this is a combination of some genetic predisposition and many environmental factors as well. And obviously, environmental factors we can modify and control.
STEPHANIE: Right, right. And actually Morgan is a fraternal twin, so I don’t know if there’s any relation with fraternal versus identical.
DR. MOSS: No, there isn’t. That’s a good…And you’re right. There wouldn’t be any genetic association with the fraternal twins, but our experience with identical twins that has allowed us to sift out a little bit of the environment versus genetics question.
STEPHANIE: Right, right. So, I guess, if you could maybe talk a little bit more about your findings in this study and, and sort of, where you see the research going in the next few years?
DR. MOSS: So, it’s been a series of studies and we have been fortunate enough to identify some very promising markers in the urine, which is encouraging because that’s easy and safe to collect, and it’s non-invasive.
DR. MOSS: And in a pilot study that involved about 45 patients, we were able to identify three urine biomarkers that when they reached a certain level, it was very highly predictive of the progression of surgical NEC, or almost a 100% predictive. Now, I don’t want to overstate that because it’s pilot information on a small number of patients. And for these initial studies, we were only able to get approval to do a single time point—so a single sample. So, what we really need to know is…would these levels change over time in a baby that we were following and would they allow us to trigger point to jump in and do something different with respect to prevention or treatment. So, I put these findings in the category of very encouraging, in a field where we need encouragement, but nowhere near a done deal, or ready for prime time use in real-time patient care.
STEPHANIE: So then, I guess, what would be your next steps with this?
DR. MOSS: So, a couple things…The first next steps would be to try to duplicate, not duplicate, but try to further study these biomarkers in one: a larger sample of patients, and two: at multiple time points. And frankly, that’s scientifically doable, and it’s a funding issue for us right now. It’s relatively doable to do a pilot study in one institution. It’s a whole different situation to do a larger study in multiple institutions.
STEPHANIE: And actually, that’s one of the other things I wanted to chat with you about is funding for research because part of our hope with this podcast is to draw attention to the need for funding in research for NEC and also, I guess, how you’re…not how you’re getting your funding but, you know, ideally…how you’d be getting your funding and, you know, anything that you’d like to speak to with respect to that.
DR. MOSS: Yeah, so I’ll give you a kind of long answer because you asked a really important question that I think people need to really understand. And I’m going to divide the answer into not for profit, either governmental or foundation funding, in one category, and then potential industry funding in another category because they are different issues. So, if I talk about biomedical research in general—the vast majority of crucial and meaningful discoveries out of biomedical research in the US have come from National Institutes of Health (NIH) and/or foundation funding. And that’s been a wonderful mechanism, and it’s contributed in substantial ways to essentially placing United States number one in terms of biomedical research and new discoveries. We are at a real low point in NIH funding at this point. And it’s due to all the other fiscal constraints that have happened in the government really since 2008. That’s when the downturn started, and NIH funding has either taken a dip, or remained flat since then, without even corrections for inflation. So, in 2006, if you were a scientist competing at the highest level for NIH funding, so these are the best scientists in the country, and you submitted a grant, you had about a 20% chance of that getting funded. In 2015, if you are the same scientist submitting the same work, you’ve got about 4 to 5% chance of getting funded.
STEPHANIE: Oh, wow.
DR. MOSS: So, essentially 95% of what’s getting submitted is not getting funded. So, not only is important work not being done, you can imagine the amount of intellectual energy and time and emotional energy that scientists are spending writing unsuccessful grants instead of being in the lab doing the work. So, I don’t want to use hyperbole and say it’s a crisis, but it’s a pretty significant problem in biomedical research right now. So, that’s the issue with the not for profit funding. If I turn to industry issues, there’s a lot of talk in the research community about the importance of developing industry relationships. And those partnerships are…can be very meaningful, and many wonderful and crucial discoveries have come out of industry-funded studies. There’s a real challenge with respect to problems in neonates, and problems in premature infants. Because the market share, or the return on investment, for these companies, even if the work is successful, is an order of magnitude below what it would be in the adult world. So, developing a highly-successful drug that helps a ton of preemies is a spit in the ocean compared to a drug like Viagra, or an antibiotic that’s used widely in adults. And, you know, these are for profit companies that are accountable to their shareholders and they have to take those factors in the account when they make decisions.
STEPHANIE: Right, right.
DR. MOSS: So, that’s a real challenge, and always will be a real challenge, and the FDA’s (Food and Drug Administration) helped us a little bit by making the orphan drug and orphan device pathway for rare diseases a little bit smoother and easier and that helps. I don’t want to say it doesn’t help. But again it only gets us 5% of the way that we need to get in terms of us developing new therapies for these babies.
STEPHANIE: Right, right. Which is one…like I said, one of the reasons we wanted to do this podcast and one of the reasons that we actually started Morgan’s Fund, The Morgan Leary Vaughan Fund, is to promote research and to try to be an avenue of funding. You know, when we get a little larger.
DR. MOSS: No, and I really compliment you, or your vision, in trying to do that because, I mean, it’s a crucial need that the fund and the organization are trying to address. And, this is a tough time right now for anybody doing biomedical research. It’s an order of magnitude more challenging if you’re trying to do something in neonates or premature babies.
STEPHANIE: Right, right. So I guess, is there anything else that you would like to add with regard to your research, or funding in general for NEC research?
DR. MOSS: So, I am more of a clinical/translational researcher, so my research tends to involve patients, or patients’ fluids and biologic markers in patients. There’s another whole side of NEC research, which is crucial, which is the basic science research, which is either in tissue culture or in animal models, which is critical to dissecting what we call the “pathophysiology”, or what’s going on at a molecular level with this disease. And of both of these lines of research are complimentary. If we are really going to make a difference in this disease, it’s innovation, findings, and contributions from both sides of that street. So, I think you’ve talked to some other doctors in other podcasts, who pursue basic science research, and I just want to make the point that we need both.
STEPHANIE: Right, right. Well, if there’s anything else that you would like to add, I would like to thank you for joining us today, and hope to speak with you soon, and appreciate all of the hard work that you’ve done, and let you know that I think your vision, and your work at Yale, really planted the seed for what became The Morgan Leary Vaughan Fund. So I thank you, and Morgan thanks you, and I think you guys are doing wonderful work.
DR. MOSS: Well thank you for your kind comment, Stephanie. I thank you, and everybody involved with the fund and the foundation, for what you’re doing. Very few of us can personally relate to what it means to lose a child, but to be able to take event and turn it into something so positive. I really compliment you, and you’re a great friend to people like me, who have devoted our life to research in this area and want to make a difference for these babies. So, I really just thank you for everything you’ve done.
STEPHANIE: Thank you. Yeah, we’re hoping to be a complimentary piece to the puzzle, and do our part to help find a cure, or a 100% prevention, for this. So, thank you.
DR. MOSS: Well, it’s a pleasure talking with you, and I appreciate your time. And wish you the best of luck with your vision for The Morgan Leary Vaughan Fund.
STEPHANIE: Thank you. And, hopefully we’ll talk to you soon.
DR. MOSS: Thank you very much.
STEPHANIE: For more information about Dr. Moss and his research in NEC visit: nationwidechildrens.org. A direct link can also be found in this episode’s show notes.
In closing, I would like to take a moment to clarify one of Dr. Moss’ comments: although we experienced NEC firsthand with Morgan, I can only imagine experiencing the death of a baby.
The Morgan Leary Vaughan Fund was named in celebration of our son’s survival, courage and strength. We noticed that most of the time organizations are formed due to loss of a family member. The Morgan Leary Vaughan Fund was founded because we know how lucky we are that Morgan not only survived but has also thrived since his bout with NEC.
It is our hope that through increased awareness and support of research that someday very soon no baby, no family will experience NEC.
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 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. Moss’ research in NEC at Nationwide Children’s Hospital by visiting http://www.nationwidechildrens.org/giving
Note: Donors should write Moss 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 Moss NEC Research on the memo line of their check.
Copyright © 2015 The Morgan Leary Vaughan Fund, Inc.
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