Physician Scientist Carries on Legacy of UH Rainbow in Neonatal Care

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Dr. Dan Simon (Host): Hello, everyone. My name is Dr. Daniel Simon. I am your host of the Science@UH podcast, sponsored by the University Hospitals Research and Education Institute. This podcast series features University Hospital’s cutting edge research and innovations. Thank you for listening to another episode. Today, I am happy to be joined by our guest, Dr. Cynthia Bearer.

Dr. Bearer is the William and Lois Briggs Chair of Neonatology and the Chief of the Division of Neonatology at University Hospitals Rainbow Babies and Children's Hospital and a professor at Case Western Reserve University. She is a renowned physician scientist investigating fetal and environmental pediatric health. She has been recognized as one of the best doctors of America since 2017 and is the 2019 recipient of the Children's Environmental Health Network Child Health Advocate Science Award.

Welcome, Cynthia.

Dr. Cynthia Bearer: Good morning.

Dr. Dan Simon (Host): Well, it's great to see you today, and before we get started in talking more about your own research, tell me a little bit about the history of the Rainbow NICU and what the NICU is like today in 2023; certainly a busy place.

Dr. Cynthia Bearer: Yeah, the NICU here at Rainbow has a very long and rich history, started by some of the best known people in neonatology, including Marshall Klaus, who, was way before my time here, although he was one of the people that actually got me to come here in the first place, and then, of course, Avroy Fannaroff, Richard Martin, Maureen Hack.

Avroy Fannaroff and Richard wrote the textbook on neonatology perinatal medicine and are very instrumental in understanding the control of respiration in our preterm babies. Maureen Hack was a person who followed our graduates for three years. Actually, she even has a cohort of infants that she has followed until their 20s and 30s to find out what is the impact of being a preterm infant in your adult life and has published very interesting results from following that cohort.

We then had Michelle Walsh who became our division chief. Michelle, for a long time, along with Avroy Fannaroff, ran the research here in our NICU, as a founding member of the Neonatology Research Network, funded by the National Institutes of Health, the National Institute of Child Health and Human Development, and I'm happy to say that Anna Maria Hibbs now is that PI, and we are continuing to be, I think, the only NICU that has continually been involved with this network since its conception.

Dr. Dan Simon (Host): Yeah, it's really exciting. So, I think I recall you have over 87 NICU beds and you have a survival that's, I think greater than 96%. So tell us a little bit about that. It's remarkable. How long it's come since I was a medical student for sure.

Dr. Cynthia Bearer: Yeah, well, I guess, you know, that, initially in neonatology, we put all our babies in one room. They were small, so we could really cram them in there and then we began to worry that the environment that that created was not the best for the outcomes of our babies…and Rainbow was one of the first places that went to a single family room where the parents can actually room in with the baby. We did that, I believe early in the 90s. It again predated my first coming to Rainbow in 1994. We, soon after that, had our single family room for our step down unit. And that then led to us doing a single family room model in our acute side, actual neonatal critical care unit. This allows mother and the father and the other family to stay with the baby all the time. We are beginning to realize that that bond is really important to the outcomes of our babies. That even though they should still be in the womb, it helps to have the mother there with kangaroo care holding, where they're doing skin to skin care. The provision of breast milk is really key to the outcome of our babies… and so some of these changes just in the physical environment has led to changes in the emotional environment, I would say, of our babies and has improved their outcome. And definitely our survival rate is one of the best in the country. And, we were scored in the top 10 of the NICUs in the country in the U. S. News and World Report this last year.

Dr. Dan Simon (Host): Well, congratulations to you. You know, I'm was very close, to Betty and Quentin Alexander, and it's so great to know that their name sits on that, NICU today. So in looking at your research history, it has certainly covered a lot of ground. Is there a common theme, in your research projects?

Dr. Cynthia Bearer: That's a common question that I get. I think there is a theme there and it, comes from my own childhood. I was not a preemie, by the way, but I was a very outdoors girl, very much involved with nature, animals, and that kind of naturally led to taking a lot of science classes and math classes. I was a math major, which has stood me very well in terms of statistics and study design and things like that. And so I went on to get a PhD here in biochemistry, sort of following that, pathway, but then I recognize that there were things that were changing in the environment that probably were not conducive to child health and fetal development. And so I went back to medical school and did my training and became a neonatologist and came here to Rainbow and began to look at how the environment interacts with fetal development and child development in specific ways. So pretty much everything that I do looks at that environmental impact on the child, particularly focusing on the brain.

Dr. Dan Simon (Host): So how did you get to the study of how alcohol, and specifically ethanol causes fetal alcohol spectrum disorder? How did you get involved in that area?

Dr. Cynthia Bearer: Well, I was trying to think of environmental exposures, and you know, most pregnant women don't realize they're having an environmental exposure. So it's really very difficult to study in a population unless you have a huge population and you're doing environmental monitoring. But ethanol is different. Ethanol is actually ubiquitous to our environment. We particularly know this after the COVID epidemic, because all of us have been dousing our hands in 67 percent ethanol for a while. But you can ask a woman or a person how much ethanol they've been exposed to by asking them how much they've been drinking.

So ethanol is the common ingredient in wine, in beer and in hard alcohol. And so we can get some kind of idea of the exposure. And I began to look at the mechanism then of why drinking alcohol during pregnancy actually results in a syndrome called fetal alcohol spectrum disorder now, it was fetal alcohol syndrome, and then we realized that smaller amounts of alcohol, can actually cause effects too. And the name changed to fetal alcohol spectrum disorder. And I also realized, that I could actually track, the exposures by looking at meconium, which is the first stools that babies pass after they're born, and actually is accumulated in utero. So you can get a track record over the last third trimester over exposures if you look at compounds in the meconium.

So I had two things going. One, looking at the mechanism of how ethanol caused brain difficulties. And secondly, looking at a biomarker that could tell me who was getting exposed…So that's how I kind of get started on fetal alcohol spectrum disorder.

Dr. Dan Simon (Host): Wow. And so, you know, we certainly have reviewed some of your papers and now you've gotten down to the fact that... neurotoxicity is related to the disruption of lipid rafts. What are they and why is it important? And I understand that you now have a biomarker from those lipid rafts.

Dr. Cynthia Bearer: So lipid rafts, which is kind of a neat name for them, were originally thought of in the early 1990s…about the time I came to Rainbow…and they were thought of as rafts, like river rafting, on the sea of the phospholipid bilayer of the plasma membrane. So they are micro domains within the plasma membrane that attract signaling molecules to come together on this platform so that they can signal to each other. And this signaling is particularly important in brain development. The area that I study is looking at the lipid rafts at the end of growth cones of neurons that are extending nerves to synapse on another nerve cell. So you have communication in the brain, and lot of the molecules are under control of these lipid rafts...So, in our initial experiments, looking at cell culture, we found that ethanol exposure, actually impaired the ability of proteins who were dependent on lipid rafts to traffic through the lipid raft. And then we looked in our animal models for this and we found the same thing. So that has set me up for the next 20 years of my research program… is looking at the function of these lipid rafts and trying to understand their biology.

Dr. Dan Simon (Host): So obviously, now you're giving us a hint that the crawling of neurons and formation of synapses, which is how we traffic and the brain is disrupted by ethanol. And I guess the question that all of our listeners would want to know is from this information, is there a way to prevent this neurotoxicity? Is there some compound, some magic bullet that a pregnant mother could take if there was a sense that, this could be an issue?

Dr. Cynthia Bearer: So I'm rather biased in this area, in that, as other scientists began to look at this in animal models of fetal alcohol syndrome they found that if they supplemented them with an essential nutrient called choline, that they could decrease the impact of ethanol on the animal's behavior.

So we took this into the lab and treated our cells with choline and then exposed them to ethanol, and found that we could also prevent the effects that we saw both on the lipid raft and on the behavior of the animal that had been exposed to alcohol. There are studies now that have been done looking at kids who have fetal alcohol spectrum disorder in the Ukraine and treating them with choline and now a four-year follow-up from these children show that the choline actually improved their behavior and their cognitive function. And there's a trial now going on in South Africa where pregnant women are being treated with choline to see if that will improve the outcome of their pregnancies.

So, we're interested in choline because it's a precursor for those lipids that are very important in lipid rafts. And we think the mechanism of choline is through increasing the resiliency of lipid rafts to the effect of ethanol. That’s one of the mechanisms probably. Other people are looking at the epigenetics effect of choline, which becomes a one methyl donor in a different metabolic pathway.

So, choline may be multifunctional and multi-mechanistic.

Dr. Dan Simon (Host): That's really great. So is there any evidence, just out of curiosity, that you can have a choline deficient diet? I mean, could it be that if you have low choline, drinking even very little amounts of alcohol, you know, say a glass of wine for some special celebration would be really bad, could you measure choline, for instance, in the pregnant mother and find out that supplementation would be a good idea?

Dr. Cynthia Bearer: Well, we're attempting to do that right now, but not looking at pregnant women. We're collecting the discarded blood from the first blood draw of infants at 24 to 28 weeks, which is about where our rat model is exposed to alcohol and determining the amount of choline in that blood and seeing if there's any social determinants of health that actually influence that amount of choline.

The major dietary source of choline is in egg yolks and there was a study done… probably Dan, as a cardiologist, you, know what the study is…the Framingham study looked at things in the diet or looked at different factors and what increased the risk for heart attacks and strokes. And one thing was cholesterol and eggs and egg yolks have a lot of cholesterol. And so people were told not to eat them. Now I don't know what the choline levels were historically before this, but the choline levels now are lower than where the FDA says they ought to be, where our RDA says that our choline concentration should be. And it's been reported that pregnant women are commonly choline deficient. It's been reported that preterm infants are commonly choline deficient and become even more deficient when they're in our NICUs. And the current standard of care does not have any choline supplementation in it. So this is concerning to me and so we're testing that it's still the same condition that people are still deficient in choline to see if a choline supplementation program in a randomized controlled clinical trial might be the next step in showing better outcomes for our very preterm babies.

Dr. Dan Simon (Host): Wow. It's really cool. So how about the connection between your work and also bilirubin? You know, we certainly know that kids go under the lights if their bilirubin is elevated and the concern obviously is, neurotoxicity. How does this connect to that? And how do your findings translate into potentially improving the outcome for preterm babies?

Dr. Cynthia Bearer: Well, back when we were discovering that ethanol had this effect on lipid rafts, we began to worry about other, chemicals like fat, lipophilic chemicals, so bilirubin is one of those. We also looked at some other common solvents like toluene, which is ubiquitous in household cleaners and agents that everybody uses in their home. And chlorhexidine, which is an antiseptic that's been very popular in terms of decreasing infections, both perioperative infections. So we looked at those and they all affected the lipid raft, and they all affected the ability of lipid raft dependent protein to mediate the outgrowth of these neurites. So we became very concerned about them and the one that I chose to go further with was bilirubin, although people are now not using chlorhexidine in babies where it can penetrate into the bloodstream because of this concern that it might be neurotoxic. So with bilirubin we can treat it with phototherapy, although the studies that came out from the Neonatal Network, which we participated in, showed that phototherapy in babies that weigh less than 750 grams actually increased their mortality, and that the improvement in neurodevelopment may have been because the babies that were going to be more affected by bilirubin in their neurodevelopment died rather than survived.

Bilirubin is a very potent antioxidant and so one reason why babies all get more bilirubin than you have in childhood or regular newborns is to stave off the oxidant effect until your natural antioxidant systems can get turned on. So bilirubin has a good side to it, but what we want to do is reduce the bad side of bilirubin. And we think that the bad side part of it anyway, is this disruption of lipid rafts.

So, in my laboratory, we also have studied this on our brain cells, and we've studied this in an animal model of hyperbilirubinemia and we find the same thing with ethanol, that the lipid rafts are disrupted, and actually the choline supplementation decreases the disruption of the lipid rafts and vastly improves the behavior of these animals on several behavioral tests that we've been able to do.

So we're hoping to move forward with this with more NIH funding, look at different parts of the brain, not just the cerebellum, and see if it's a more of a global effect and try to determine the mechanism.

Dr. Dan Simon (Host): Wow. So this is, so inspiring to me as a vascular biologist, we try to go from bench and animal model to bedside, and it's difficult. But it sounds like, you're really making incredible progress with translational studies and your studies with choline are very, very interesting to potentially reverse this neurotoxicity. I want to thank you for taking the time to speak with us today, Dr. Bearer. It's been a, privilege to listen to you. The Fannaroff Martin textbook still looms large. I think what it's in its 12th or 13th edition.

Dr. Cynthia Bearer: Yeah I think the 13th I think.

Dr. Dan Simon (Host): 13th, and I'm really glad that Rainbow is continuing to be a leader in the NICU.

For our listeners interested in learning more about research at University Hospitals, please visit universityhospitals.org/research. Thank you very much.