Announcer: From the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health, welcome to another installment of NICHD Research Perspectives. Your host is the Director of the NICHD, Dr. Alan Guttmacher.
Dr. Alan Guttmacher: Hello, I'm Alan Guttmacher. Thanks for joining us for another in our monthly series of podcasts from the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health.
My guests today are Dr. Constantine Stratakis, Dr. Steven Coon, and Dr. Katie Laughon. We'll talk with them today about several recent studies: first, a new finding on how certain tumors stimulate the production of red blood cells; next, how long stretches of DNA, once thought to be inactive, influence the response to day and night cycles; and finally, a study investigating whether it is safer for extremely preterm babies to be delivered vaginally or by cesarean section.
Our first guest, Dr. Constantine Stratakis, is the director of our Division of Intramural Research here at NICHD. Constantine was part of a research team, which discovered a genetic mutation that appears to increase production of red blood cells in certain tumors. That discovery may shed light on how some tumors regulate their blood supplies to sustain growth. Constantine, could you tell us more about this study?
Dr. Constantine Stratakis: So, the hypoxia-inducible factors, or HIFs, are molecules that are involved in controlling energy, iron metabolism, red cell production, and development. When these proteins are dysregulated, they contribute to tumor formation and cancer progression. One of the investigators in the Division of Intramural Research at NICHD, with whom I work very closely together, Dr. Patrick, studied one of my patients and another of his patients and found mutations in the genes in coding the type 2 alpha subunit of hypoxia-inducible factors. This molecule is known as HIF2A. No mutations of this gene have been linked previously to tumor formation. The two patients, one presented with a tumor that increases blood pressure and causes other symptoms that are related to endocrine abnormalities, and the other patient had actually one of these tumors in addition to a classic endocrine tumor, known as somatostatinoma because it produces a hormone known as somatostatin. Both patients had increased red cell production. We found mutations that increased the activity of the molecule and it's not exactly clear, this is a new finding on how this is done, but we did find in the laboratory that these mutations prolonged the presence of the molecule in the cells. So it prolonged what you call a half-life of this molecule, and so therefore the action of the protein was prolonged. We think that because of the prolongation of the action of the molecule, there was a contribution to an increased blood supply, increased oxygen supply to the tumor and therefore contributing to the tumor growth. It is unclear on how cell perforation is controlled by this, but clearly vascular supply and red cell action was increased. So clearly, more studies need to be done in animal models and in the laboratory to extend this observation and investigate its causative role in tumor formation, but it is a significant new discovery in this field, opening up a really new venue of investigation.
Dr. Guttmacher: Dr. Stratakis, is it likely that this genetic mutation is unique to the rare tumors these two patients had, paragangliomas and somatostatinomas?
Dr. Stratakis: You know, as I said, this finding has to be replicated in other patients and similar tumors, and so at this point it's unclear whether similar mutations make cause other tumors. What is clear is that the tumors that we found these mutations in, paragangliomas and somatostatinomas, are highly vascular, so one would expect that if this mutation does cause the increased vascular formation in these tumors, that other tumors that are highly vascular may harbor similar mutations. So I think I would look for these mutations in tumors that have a similarly increased vascular supply.
Dr. Guttmacher: So then how might this finding influence research in other types of tumors and to maybe even find better treatments for tumors?
Dr. Stratakis: You know, hypoxia-inducible factors, HIFs, are very, very, essential molecules that control energy, metabolism of the cells, and the development of tissue cells, and so these mutations are the first for any class of these molecules to be linked to tumors, really the first mutations of the HIF subclass of molecules. Therefore, this discovery is important for both for the field of tumor biology as well as for therapeutics since these molecules now can be targeted specifically for new treatments of tumors that have this increased vascular supply.
Dr. Katie Laughon: I have a question for you. So does the production of these HIFs that's producing too many blood cells, does this help the tumor to survive or grow?
Dr. Stratakis: So again, we would have to develop an animal model and try to test this in vivo in an animal model and see how it does contribute, but almost clearly what happens is that somehow the cells sense that there's more blood cells in there and either because there's more vascular supply or because there's more blood cells that have been produced because of these mutations. We think that that is what causes the tumor, but it will have to be done in the lab to try to see exactly how it happens in an animal model. So the creation of an animal model of these mutations is essential both for understanding how it causes tumors as well as for developing therapeutics.
Dr. Guttmacher: Thank you, Constantine. That's a good example in fact of where having animal models to really understand human disease and to design interventions for human disease can be crucially important. Thanks. Our next guest, Dr. Steven Coon, is also a scientist in NICHD's Division of Intramural Research in its Section of Neuroendocrinology. Along with that Section's Dr. David Klein, Dr. Coon's part of a research team that explored what has often been called the "dark matter" of the genome—the more than 98 percent of our DNA once thought to have no function. But Dr. Coon and his colleagues found that these dark matter DNA regions are anything but inactive. In fact, they appear to contain information of crucial importance for controlling the body's response to day and night cycles. Dr. Coon, could you please tell us about that study?
Dr. Steven Coon: Sure. This study is really about our basic 24-hour biological clocks. We have this master clock in the brain that tells us it's time to sleep or wake up or eat. Actually if you were in a room with no windows so you couldn't tell what time it is outside, your body would still want to eat and sleep on its normal schedule, the clock is that strong and reliable. Understanding and controlling this clock is important because when our internal clock and the external environment are not synchronized, we can feel the negative effects such as jetlag or problems adjusting to shift work. One of the major ways that this master clock in the brains tells the rest of the body what time it is, is by stimulating another part of the brain called the pineal gland to produce melatonin. And it produces melatonin on a cycle that's high at night and low during the day, and that's how the body knows what time it is. This small pineal gland is a factory for producing melatonin at night and this master clock stimulates the pineal to crank up its metabolism at night and this actually involves turning on the activation of many genes—in fact hundreds of genes are turned on at night—and then toward dawn everything is quieted back down and the pineal gland gets ready for the next cycle. What we have been studying is how this large number of genes in the pineal gland gets activated or mobilized so quickly in such an organized fashion. This is where this dark matter DNA comes in. This dark matter, as you said, is about 90 percent of our genomic DNA or chromosomes that's not used as a template for producing the RNA that's turned into proteins that actually perform most of the functions in the cell. Mostly we have no idea what this dark matter DNA does, in fact it used to be called junk DNA, but now we know better of course. Earlier studies on this dark matter DNA show that what little is known about the RNA that's produced from it, points to a role in controlling which genes—these are what's contained in the other 2 or 3 percent that we know about in the genome—which genes are turned on and which genes are turned off, and this usually involves turning them on and off in long-term processes such as development or cancer. What we wondered in this study was whether or not this dark matter DNA might also be functional in controlling a highly dynamic process like what we see in the pineal glands, so many genes are turned on and turned off on a daily cycle. In this study that was recently reported in the Proceedings in the National Academy of Sciences, we identified over 100 long stretches of this dark matter DNA that produced RNAs that don't code for proteins but cycle up and down on a daily cycle in the rat pineal gland. And this is exciting. In fact we even showed that if you put the animals into constant darkness conditions, these RNAs that are coming from the dark matter DNA still continue to cycle up and down. This kind of cycling and responsiveness has never been seen on such a scale, and that is what is exciting about this work. We hypothesize that at least some of these long non-protein-coding RNAs that are produced from this dark matter DNA are orchestrating a large scale of changes in gene expression that we see in a pineal gland that we see on a daily basis. So this research opens up a whole new vista for understanding how genes might be controlled by this dark matter DNA or dark matter RNAs on relatively short time scales.
Dr. Guttmacher: So Steve, do these findings offer any implications for the health of shift workers and people who frequently travel between time zones?
Dr. Coon: Well, sure, because the problems that you described are caused by this conflict between the clock and the external environment, the more targets that we have for manipulating or controlling the clock, the better off we are. So these new dark matter RNAs actually provide new therapeutic targets that we can use for helping people to deal with shift work or jetlag or situations like that.
Dr. Guttmacher: Thank you, I enjoy both the science and now the next time I have jetlag, I'll somehow feel a little bit more comforted knowing something about why I'm having it. So thanks for that, Steve. For our final topic, we will talk about a study that compared early preterm birth outcomes for cesarean and vaginal deliveries. Dr. Uma Reddy of NICHD's extramural Pregnancy and Perinatology Branch is the primary author of a study that found vaginal delivery to be as safe as cesarean delivery for infants born early preterm, provided the fetus is in the head-first position at the beginning of labor. Uma is on travel for NICHD today, so one of her coauthors on the study, Dr. Katie Laughon, is here with us today. Dr. Laughon, can you please describe the study findings for us?
Dr. Laughon: Well, sure. We know that early preterm fetuses are more fragile and so there's been some controversy about the best route of delivery for them. There is thought that a cesarean delivery could prevent death from possible trauma that might occur from labor and vaginal delivery; however, it's also known that cesarean delivery can be associated with more morbidity for neonates, in particular respiratory difficulty. Six randomized trials have been attempted in the past but they had difficulty recruiting enough women. In observational studies, while they had a larger number of women in the studies, they had conflicting results and part of the issue was that most studies because of the lack of detailed information only were able to investigate the actual route of delivery instead of the attempted route. So, for example, they only studied whether a woman had a cesarean delivery, but they weren't able to take into account whether she actually labored and tried to have a vaginal delivery first. So therefore, we studied the risks of neonatal mortality by attempted route of delivery in the Consortium on Safe Labor, which is a large cohort of over 200,000 women who came into labor and delivery and delivered. And of the women in this study there were about 2,900 women who delivered at less than 32 weeks of gestation and had singleton pregnancies and were eligible for our study. And what we found was that for fetuses in the vertex or head-first position, there was no difference in neonatal mortality with attempted vaginal delivery compared with a planned cesarean delivery. And moreover, 84 percent ended up delivering vaginally, so these attempts were highly successful. Of the breech pregnancies, only about 30 percent of women attempted vaginal delivery and, depending on the gestational age, between 17 and 28 percent were successful. However, a planned cesarean delivery was associated with a lower mortality with delivery at less than 32 weeks.
Dr. Guttmacher: That's very interesting and obviously mortality and other immediate outcomes are of great importance, but do we know anything from this study about the long-term outcomes for both the mothers and the infants from each group?
Dr. Laughon: Well, that's clearly an important area, but our study wasn't able to address long-term outcomes. We do know that morbidities in the neonatal period are associated with increased risk of adverse long-term outcomes. So future work is needed to determine how the route of delivery could affect children long term.
Dr. Guttmacher: That makes sense, but do you think these findings alone might influence current clinical practice?
Dr. Laughon: Ideally we would want data from a randomized trial as well as more long-term follow-up data. That said, our study provides the best data we have to date in order to guide clinical management. For women in these early preterm gestational ages, when the baby is head first, it does seem that a vaginal delivery is highly successful and a safe route. But ultimately, women should talk to their doctor about the benefit and risks of attempting vaginal delivery in this situation.
Dr. Guttmacher: Katie, I see that Dr. Coon has a question for you.
Dr. Coon: Women considered at immediate risk for preterm labor are often given a course of antenatal corticosteroids to help the infant's lungs mature. Did your study find any differences in survival between the attempted routes of delivery when you took into account whether the mothers had received antenatal corticosteroid treatments?
Dr. Laughon: So only about five sites in our study recorded this information that we were able to capture from the medical records, so it was a much smaller group. But we did analyze the outcomes in these sites that reported that information, and we found that for the really early deliveries, between 24 to 27 weeks of gestation, we got the same results. There was no change in neonatal mortality when we took antenatal corticosteroid administration into account. There were too few deaths in the later deliveries, between 28 to 31 weeks, so we weren't able to evaluate the effects of steroids in that group.
Dr. Guttmacher: Thank you, Dr. Laughon. That brings us to the end of our podcast for this month. I'd like to thank Dr. Stratakis, Dr. Coon, and Dr. Laughon for joining us today—and for sharing with us some of the research they are conducting at the NICHD. I'd also like to thank our podcast listeners for joining us and for your interest in the work of NICHD.
For more information on any of today's topics and many related topics, visit www.nichd.nih.gov. That's www.nichd.nih.gov.
I'm Alan Guttmacher, and I hope you will join us for more NICHD podcasts as we post them on our website each month."
This has been NICHD Research Perspectives, a monthly podcast series hosted by Dr. Alan Guttmacher. To listen to previous installments, visit nichd.nih.gov/researchperspectives. If you have any questions or comments, please email NICHDInformationResourceCenter@mail.nih.gov.
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