Right From the Start
Exploring Causes and Cures for Prematurity
One group of investigators at Cincinnati Children’s believes the course of a premature birth may well be set from the very beginning – the time at which the embryo implants in the uterus.
“I’ve always thought, there is such a short window for implantation, it must be very critical,” says SK Dey, PhD. “Why did nature determine that period – why not implant at random, at any time? There must be some meaning why implantation must occur at such a defined time.”
Dey set out to answer the question by devoting his career to unraveling the underlying signaling mechanisms that the determine that precise time. He arrived at Cincinnati Children’s this past summer to launch the Division of Reproductive Sciences, where he and his team continue this investigation.
At the heart of his research is the theory that there is an ideal window of time for a fertilized egg to implant, and in humans, that window is very short – no more than two to three days. Implatation outside this window can cause problems for the short and long-term health of the baby.
“In humans, implantation occurs two or three days during the luteal phase – day 21 to 24 of a woman’s cycle. It’s a very short window,” Dey says. “If implantation takes place after that window, there is evidence that many of the pregnancies fail. We know from our previous studies that the window of implantation is critical for the success of pregnancy and the well being of the offspring.”
And that well being extends far beyond childhood, he believes. “There is already evidence that obesity and heart disease are determined by life in utero. In short, the quality of the implantation determines the quality of pregnancy, and the quality of pregnancy determines the well-being of the offspring and their adult life.”
He bases his concept on a series of genetic and molecular studies utilizing genetically engineered mouse models. “We have found that several molecules are involved - signaling pathways that determine the fate of implantation in the uterus.”
Crucial Signals
Although much of his research has focused on the role of female hormones in the implantation process, another significant finding of Dey’s studies is a key role played by endogenous cannabinoid-like molecules in reproduction.
Endocannabinoids are liped molecules produced naturally in the body that act as neurotransmitters in the brain. They are the same chemicals responsible for the cognitive changes produced by marijuana – perhaps a better-known source of cannabinoids - but in this instance they serve a very different purpose of signaling the uterus for implantation.
When it comes to ensuring a healthy pregnancy and a healthy future, timing is everything says Dr. SK Dey.
Dey’s lab is focusing on one particular endocannabinoid called anandamide, which is produced in the uterus and seems to play a key role in determining the optimal timing and readiness of the uterus for embryonic attachment. Dey’s team is primarily leading the study in this country exploring endocannabinoid signaling in early pregnancy. In studies with genetically engineered mice, they have found that it is crucial, and that the balance must be just right.
“These endocannabinoids interact with two receptors, CB1 and CB2, and what we have found is that the absence of these receptors results in major disturbances at various phases of pregnancy,” Dey says. One of these disturbances includes premature labor and the resulting problems it causes.
By better understanding the factors that define the ideal time for implantation, Dr. Dey believes researchers will be able to lengthen the time and minimize the risk that comes when an embryo embeds at the wrong moment.
He believes his findings will be especially helpful in treating infertility.
“One of the problems with IVF programs, they don’t know when the window of implantation is open," he explains. "They just transfer the fertilized embryos to the uterus. If they know a good marker when the uterus is ready for implantation, that will be a big boost.”
While Dey’s team’s findings may provide a significant piece in completing the complex puzzle of too-early birth, he admits there are still many pieces missing.
“We never realized the problems could occur so early. We always thought prematurity was caused by infection or inflammation, which I’m sure are also factors. But without infection or inflammation, there is still prematurity. So there must be other reasons.”
A New Look at Infection
Can some level of infection in utero actually help fetal lungs to mature? Dr. Alan Jobe is working on finding out.
Exploring the part that infection plays in premature birth and fetal lung development is the work of Cincinnati Children’s physician and researcher Alan Jobe, MD, PhD. Doctors have long known that chronic indolent infection in the womb is one cause of premature birth. The theory is that when a fetus is exposed to infection while still in the womb, the environment becomes so hostile that the infant basically jettisons early, opting for chancy survival outside rather than facing serious harm or death from within.
“More than 50 percent of infants born at less than 30 weeks gestation have been exposed to infection and inflammation in utero – they are thought to be the major causes of preterm delivery,” says Jobe. “We are exploring how the fetus responds to infection and inflammation, focusing on the lung, on systemic responses, and on adapting immune response.”
Jobe has been studying the developing lung for 30 years, and how best to help these premature babies survive the assault of breathing outside the womb before their lungs are fully developed. The current standard of care for premature infants is a combination treatment with antenatal steroids and surfactant to help build lung function.
A Flip Side to Inflammation?
But one of the discoveries Jobe and his research team made more than a decade ago and that continues to be a focus of their study is that exposure to infection and inflammation in utero can actually help fetal lungs to mature.
He believes one reason for this might be that the inflammatory response is really an immunologic phenomenon, and the fetus has a very suppressed immunologic system compared with an adult.
"So by exposing a fetus to an inflammatory response, you actually modulate how the fetus responds to inflammation,” Jobe says. “The inflammation actually matures the fetal lung much more potently than the use of antenatal steroids.
His hope is that by better understanding what causes this maturation, researchers might be able to find better ways to help lungs develop in utero.
“If we can figure out how that signaling occurs, we might end up with a therapy to improve lung maturation in the fetus.”
Protecting Tiny Lungs
Jobe is also examining how the premature newborn adapts to breathing after birth. Despite clear guidelines for resuscitating full-term infants, he says, there are no clear directives for how to resuscitate preterm babies. Jobe and his team are studying various resuscitation procedures in animal models to see how the fetal lung responds, and how they might minimize trauma to the lung.
“With a premature infant, you’re dealing with a lung that’s full of fluid that you need to get to exchange gas, and you need to do it quickly, but if you are too aggressive, you injure the lung,” he says. “The problem is getting the lung to develop toward normal without injuring it so much that you prevent it from developing.”
Breathing Easier: Discovery of a Crucial Surfactant Gene
Dr. John Shannon (pictured) and fellow researcher Dr. Jim Bridges isolated the gene that makes surfactant work. Their discovery could help determine how to spur the body' own production of surfactant.
Just down the hall from Jobe’s office is fellow researcher John Shannon, PhD, who is equally passionate about finding better ways to help premature infants breathe more easily.
Shannon’s work centers on surfactant, the miracle substance produced by the body that keeps the lungs inflating and deflating with ease. Babies born before their lungs are fully developed lack enough natural surfactant, so every breath becomes a struggle.
“This surface area of the lung has a very high surface tension, like a plastic bag that’s wet on the inside,” says Shannon. “When the sides collapse together, it takes effort to pull them apart, and without surfactant it's more than a baby can muster.”
For years, artificial surfactant has been given to infants with great success, saving countless lives. Shannon calls the discovery of surfactant “one of the great triumphs in bench to bedside medicine.”
But he and research partner Jim Bridges, PhD, have delved further into the workings of this wonder substance and have identified the gene responsible for activating dipalmitoyl phosphatidylcholine (DPPC), a lipid and the key ingredient in surfactant. Their discovery could help determine how to stimulate the body’s own production of surfactant.
Gene With a Mission
Scientists have long known about the biochemical workings of DPPC. But Shannon and Bridges were able to isolate a gene responsible for its synthesis and found that it was most abundantly expressed in the lungs.
“We like genes like that,” Shannon says, “because we can go in and say, well, if it’s only in the lung, it’s probably really important for the lung.”
And it was.
Using a genetic probe, Shannon and Bridges were able to inactivate the gene in mice and when they did, it resulted in respiratory distress and death at birth. Their conclusion? “It’s every bit as important as we thought it was,” Shannon says.
Improving on a Good Thing
Understanding how the gene is regulated could not only have powerful implications for helping premature babies produce more natural surfactant, it also could help full-term infants, children and others who suffer lung injury.
“After lung injury you have some of the same problems you have with prematurity, where the gas exchange units are damaged,” says Shannon. “Maybe through regulating this gene, and up-regulating its expression so you end up with more surfactant being made, you could eventually have an effective approach for treating lung injury.”
The work continues and regardless wear it leads, it seems clear that the course of an individual’s future health is determined earlier than anyone had ever imagined, says SK Dey.
“I have always believed that the beginning determines the end. If your beginning is shaky, the end point will not be right.”
All of the physicians and researchers featured in this article also hold academic appointments in the Department of Pediatrics at the University of Cincinnati College of Medicine.
