Researcher gets major funding to investigate premature births

Brown’s laboratory at Wright State is one of only a few labs in the world with the ability to use so-called lentiviral technology to introduce a gene into specific placental cells of an animal to look at their function.

The National Institutes of Health recently awarded Thomas L. Brown, Ph.D., an associate professor in the Department of Neuroscience, Cell Biology and Physiology at Wright State University, a five-year grant of more than $1.5 million to investigate the underlying factors that can cause preeclampsia and pregnancy-related disorders that lead to premature birth.

About 12.7 percent of all babies born in the United States are preterm, according to the March of Dimes. The rate has increased 36 percent in the past 25 years, partly because of an increase in elective caesarean sections, an increase in older mothers and the growing use of assisted reproduction, which increases the risk of multiple births. Preeclampsia occurs in about seven of every 100 pregnancies.

Preterm babies are born earlier than 37 weeks into a normal 40-week pregnancy, however exactly what causes premature births has long baffled experts.

Premature babies can face a number of challenges, including extensive hospitalization, breathing problems because of underdeveloped lungs, undeveloped organs and greater risk of life-threatening infections, as well as an increased possibility of long-term complications, according to the National Institute of Child Health and Human Development.

The conditions that lead up to premature births also pose serious health risks to the mother, causing high blood pressure and potentially kidney damage or failure.

Brown obtained his Ph.D. in Developmental Biology from the University of Cincinnati and did his post-doctoral work at Cincinnati Children’s Hospital Medical Center and the Cleveland Clinic Foundation.

Brown is fascinated by the fact that babies, and in fact all mammals, arise from one single cell, develop different features that make them unique and then at a certain point stop invading in the womb.

“If it didn’t stop, the baby would be almost the same as a cancer,” he said. “So the underlying reason for studying the placenta and pregnancy is that if you can figure out why the baby stops invading and just sits there and grows, then you might be able to figure out how to stop cancer.”

Embryos develop in about 1 to 2 percent oxygen for the first eight to 10 weeks of life, an oxygen environment in which no other animal can survive in. As the embryo grows, it moves (invades) into the uterine lining and toward the mother’s blood vessels so it can get access to blood and food. Since the mother’s arteries contain about 12 percent oxygen, the embryo slowly gets increasing amounts of oxygen as it gets closer.

“When the embryo hits about 12 percent oxygen, it stops invading,” Brown said. “So we know oxygen serves as a signal and is controlling how much it invades, when it stops and when it starts to do something else.”

Brown began looking at hypoxia inducible factor, or HIF-1alpha, a protein that they discovered responds to the changing oxygen levels in the placenta.

As an embryo, HIF-1alpha is turned on due to the very low oxygen levels. As the baby reaches the mother’s oxygen level, HIF-1alpha is normally turned off at the appropriate time, like a light switch.

Brown says it is possible that failing to turn off the light switch at the right time (and having too much HIF-1), may cause the embryo to not invade the mother’s blood vessels correctly and therefore lead to preeclampsia.

Having spent the last 11 years at Wright State working in this area, “We had gathered a lot of information that told us we were on the right path,” Brown said.

Brown’s laboratory at Wright State is one of only a few labs in the world with the ability to use so-called lentiviral technology to introduce a gene into specific placental cells of an animal to look at their function.

“We know we have the ability to alter a gene, put it specifically in only certain cells of the placenta, turn it on, let the foster animal mother carry the baby, follow the baby, follow the mother, see if she gets high blood pressure, see if she gets protein in her urine, see if the baby is born with low birth weight and prematurely,” Brown said.

“This unique technology will tell us where to look and as to what’s causing the problem,” he said. “We’re getting closer than most people know.”

His early studies indicate that in the placenta, when the oxygen-sensing HIF-1alpha gene is hyperactivated and does not switch off at the critical time during development, mice give birth prematurely to babies and they have low birth weights.

Brown cautions that not every mother who gets preeclampsia, may get it for the reason he and his research team is investigating.

“But I think in some populations of women with preeclampsia, this is what’s going on,” he said. “So it’s an exciting time. The longer you keep the baby in the mom, the better chance the baby has—even if you can extend the pregnancy for just four more weeks. That seemingly small step is a giant leap forward.”