Who's in Charge?
A new study explores whether infant or mother calls the shots before birth
In a genomic-age version of the chicken-or-egg question, neonatologist and researcher Jeffrey Whitsett, MD, is pondering what leads to premature birth and influences the readiness for survival of the preterm infant.
Whitsett is exploring the genes that trigger a baby’s too-early birth, how genes signals readiness for birth and who’s in control – baby or mother.
Why Nine Months?
Despite advances in neonatology, doctors still have little understanding about what controls the length of gestation, Whitsett says. Why does a whale need two years to develop, an elephant a year and a half, a human just nine months, and a mouse 20 days? And if a human needs nine months, what happens to cause the fetus to abandon the womb too soon? Are there systems in place to help the preterm infant survive?
Understanding how much time is needed for proper development, and what causes an infant to be born before that time is up, is a focus of Whitsett’s research. He and his team have spent years studying - and repairing - the damage caused by premature birth. His particular interest is the premature newborn’s lungs. Whitsett helped identify the genes and proteins critical for surfactant function and their role in replacement surfactant therapy. Pulmonary surfactant replacement helps infants breathe while their lungs induce the lung genes needed to manufacture surfactant - helping them to get over the hump of prematurity.
“We started with the genes and proteins critical for lung function, because they are a really big hit,” he says. “If your lungs don’t work, you’re in real trouble. By far, most perinatal mortality relates to immaturity of the lung and the problems that it causes.”
And, he adds, the lungs are one of the last organs to fully develop in utero, which is why keeping babies in the womb as long as possible is so important. “In the late weeks of gestation, lung maturation goes from nowhere - your lung looks like a liver – and within a few days, you’ve induced hundreds of genes, lipids, and changed its structure to allow breathing.”
Finding Triggers
When a baby jumps the gun and enters the world before he should, Whitsett says, neonatologists have to compensate by balancing the function of each organ until the infant matures enough to live independently. While doctors are adept at doing this, he says, there has to be a better solution – one that ultimately gets to the bottom of what triggers prematurity, and ultimately, stops it from happening.
In close collaboration with the March of Dimes, Whitsett and collaborators at Jackson Laboratories in Maine are looking for answers in strains of mice with varying lengths of gestation. The researchers search out traits that differ from one strain to another in hopes of learning what contributes to the variation in gestation times and how this influences the lung’s readiness to allow breathing at birth.
Whitsett reports that among the different strains of mice, gestation can vary as much as a couple of days. But within each individual strain, there’s little or no variation. “Each individual mouse strain delivers at the same time, within an hour or so, no matter what,” he says. “The time of gestation is genetically determined. There are genes modifying and controlling it.”
Gene Swap
But are they mom’s or baby’s genes? To find out, Whitsett and collaborators are studying two strains of mice that consistently give birth days apart from one another. The researchers will transfer the embryos from one strain into the other.
“We’ll have the genetics of the long gestation in the mother with the genetics of the short gestation,” he says.
If the mice transplanted from the strain with the shorter gestation time continue to develop for two more days, they will know it’s the mother who controls things – and who controls the readiness of the lungs.
The process is a highly precise, labor-intensive exercise that follows each day of each mouse’s fetal development down to the last detail. The scientists are especially interested in whether the lungs are ready to function independently.
The team has measured nearly 50 genes and lipids that determine lung maturity, and has found what Whitsett calls “profound” differences between the two strains in their readiness for birth.
“The strain programmed to be born early has a one- to two-day advance, which in a mouse pregnancy is like a couple weeks in a human,” says Whitsett. “Using this model, we will find whether the mother or fetus controls these programs and we’ll find the genes that program the lungs to be ready for birth.”
Who’s the Boss?
The next step will be identifying the link between the genes that control birth and those that get the baby ready. Whitsett believes their findings will extend beyond the lungs.
“This should pertain to all organs. The question will be, is the intestine also listening? Are the genes that control intestinal development also controlling the lung and the brain? The baby has to remember to breathe, to keep his temperature constant. All these things are directed by the brain. Is it the brain in the fetus controlling all these other organs, or is it the mother?”
At this stage of research, Whitsett’s hunch is that mom is in charge, although he cautions that the studies are not yet complete. Regardless, he sees the work as a platform for understanding the genetic control of length of gestation, getting ready for birth and perinatal survival. That understanding should lead to the ability to regulate things when they go awry.
“If you know the gene that’s determining how long the baby stays in, and it’s a hormone or a small molecule that’s made in some tissue, you can make an antagonist. If you know the circuitry in the timing of natural lung maturation, you can develop drugs to enhance maturation or tests for susceptibility,” he says. “This would allow us to provide markers for a woman’s risk and provide pathways that could be manipulated therapeutically to prolong gestation or to improve lung function after premature birth.”
Jeffrey Whitsett, MD, is director, Perinatal Institute; Chief, Section of Neonatology, Perinatal and Pulmonary Biology; and professor, Department of Pediatrics, University of Cincinnati College of Medicine.
