Let’s say an expectant mother arrives at her doctor’s office for a routine checkup. She’s seven months pregnant and she’s completely healthy: She hasn’t had any illnesses, she isn’t taking any medications, and she’s keeping a healthy diet.
But since last month’s visit, her baby’s weight appears unchanged.
“What do you do?” asks Yoel Sadovsky, director of Magee-Womens Research Institute (MWRI) in Pittsburgh.
Although the situation Sadovsky describes is hypothetical, it’s a scenario that plays out often in real life, and it has no easy resolution. The condition, known as fetal growth restriction, affects around 5% of pregnant women, explains Sadovsky, also a professor of microbiology and molecular genetics at the University of Pittsburgh. Its most common cause is a dysfunctional placenta.
Normally, the placenta transports oxygen and nutrients from a mother to a fetus and expels waste such as carbon dioxide. Yet despite the organ’s importance, how it develops is still a mystery to scientists.
As a result, premature delivery is often the only option when a defective placenta threatens a baby’s health, Sadovsky says. “And if you deliver the baby prematurely, you may cause major problems,” ranging from stunted physical and mental development to death, he adds.
Announced earlier this year, the Human Placenta Project aims to give doctors a better understanding of the placenta so that they might one day be able to diagnose defects earlier in a pregnancy and develop therapies. Although the project, organized by the Eunice Kennedy Shriver National Institute of Child Health & Human Development, won’t begin funding placenta research immediately, scientists, physicians, and NICHD officials have already begun coordinating their efforts.
Representatives from these groups met for two days in May to begin outlining a research road map, but this is still a work in progress, says Catherine Y. Spong, director of NICHD’s Division of Extramural Research. Broadly speaking, the project’s primary goal is to monitor the placenta in vivo and in real time by better utilizing existing techniques and by developing entirely new technologies (Placenta 2014, DOI: 10.1016/j.placenta.2014.02.012).
Much of a baby’s earliest tissue belongs to the placenta. After an egg is fertilized, some of the first cells that differentiate with specialized functions go on to form the placenta. But first, these so-called trophoblast cells must anchor a fertilized egg to the lining of the uterus.
The trophoblasts then replicate and advance into the spiral arteries of the uterine lining, stripping the blood vessels of their muscle and making them larger and less rigid. The cells continue on, penetrating deeper into the lining to form a branched network of fingerlike protrusions called villi.
Early in pregnancy, human trophoblasts are among the most invasive in the animal kingdom. Many physicians compare them with cancer cells because of the manner and extent to which they remodel the uterus. But this drastic makeover is necessary for the baby’s survival.
Enlarged spiral arteries carry a mother’s blood and nutrients to the fetus more effectively than smaller ones would. The villous network also has a remarkable surface-area-to-volume ratio, further facilitating the exchange of nutrients and waste. Trophoblasts that don’t invade completely and fail to optimize these connections can create complications such as preeclampsia or fetal growth restriction.
“Women die from these conditions,” says George R. Saade, director of maternal-fetal medicine at the University of Texas Medical Branch. “Babies die from these conditions.”
The trophoblast invasion is most intense during the first trimester of pregnancy. Placental dysfunction may start developing during this stage, but most of what researchers know about the organ comes from studying placentas that are delivered when babies are born. Some states allow researchers to study placentas from aborted pregnancies, however. The placenta 10 weeks after conception is vastly different from what it is at birth, but physicians lack the tools to monitor placental development in the womb over the complete course of pregnancy.
“It’s like trying to study neurology without magnetic resonance imaging,” Saade says. “Every day, I wish I had better access to the placenta.”
The Human Placenta Project will work to provide doctors with the tools to more fully assess placental health and development. When researchers invited by NICHD convened in May, they first discussed which available technologies could better probe the placenta. Kathleen M. Schmainda, a professor of radiology and biophysics at the Medical College of Wisconsin in Milwaukee, presented at the meeting, although the invitation surprised her.
“I thought they had the wrong person,” she says. “I said, ‘Do you know I do brain tumor research?’ ”
The organizers did, but they were interested in knowing more about how Schmainda studies tumors. Her group develops new magnetic resonance imaging techniques to visualize and analyze brain tumor tissue in living patients. Similar techniques could be applied to the placenta.
Doctors have employed fetal MRI for more than a decade, but it has seldom been focused on the placenta. And it’s largely been viewed as a complementary technique to ultrasound imaging and Doppler blood flow measurements, which indirectly assess maternal and fetal vasculature. Although Schmainda says advanced MRI may not replace these existing techniques, it has advantages and untapped potential.
“You can see beautiful soft-tissue contrast that you don’t see with ultrasound or any other radiology technique,” she says, adding that MRI could provide even more detailed information on blood flow and the vascular structure of the placenta. “That’s always been the beauty of MRI.”
Imaging the placenta offers some unique challenges, however. Fetuses move, which can ruin slow scans. Chemical dyes or MRI contrast agents allow for faster scan speeds, but their effect on the developing fetus is unclear. Employing these compounds is an option doctors prefer to avoid.
Schmainda is optimistic that developing a technique known as arterial spin labeling (ASL) will allow researchers to study placental structure and function without contrast agents. In ASL, a radio-frequency pulse magnetizes the water in blood. This magnetized water becomes a safe, endogenous MRI label without involving needles, syringes, or potentially harmful exogenous chemicals.
Still, doctors probably won’t scan pregnant women before the second trimester. “MRI is completely safe, and there’s a ton of evidence to indicate that,” Schmainda says, “but at those earliest stages, as a mom, you don’t want to do anything you don’t have to do.” To study placental development in the first trimester, some researchers are turning to chemicals that occur naturally, such as the water in blood.
In addition to fetal waste, the placenta releases proteins and bits of genetic material into the maternal bloodstream. Researchers recently discovered that as much as 15% of the RNA circulating in the maternal bloodstream has placental origins (Proc. Natl. Acad. Sci. USA 2014, DOI: 10.1073/pnas.1405528111). This and other placental detritus are likely indicators of the well-being of the fetus and placenta, MWRI’s Sadovsky says. All a doctor has to do to get at them is take a sample of the mother’s blood.
The trick is learning how to isolate these biomarkers and correlate them with placental function. This is no small feat, but some companies have already commercialized tests that screen fetuses for Down syndrome using placental chemicals released after the 10th week of pregnancy.
The placenta, however, is a taker as well as a giver. It absorbs nutrients from a mother’s blood to deliver to the fetus. Maternal blood also delivers other chemicals to the fetus, although scientists know very little about which ones breach the placental barrier. Identifying these chemicals would be a first step in correcting abnormal pregnancies with pharmaceutical interventions. On the second day of the Human Placenta Project meeting in May, Erik Rytting of the University of Texas Medical Branch explained how nanotechnology might help address this issue.
Researchers have shown that engineered nanoparticles can permeate the placenta. Rytting, a pharmaceutical chemist, now wants to learn which particles can cross the placental barrier and whether those particles can be designed to deliver drugs and signal placental health.
He’s currently exploring particles based on polylactic acid, which is biocompatible in adults and may be safe for fetuses. So far, these particles appear to be less problematic than SiO2 or TiO2 nanoparticles, which complicate pregnancies in mice, according to one study (Nat. Nanotechnol. 2011, DOI: 10.1038/nnano.2011.41). The human placenta is a unique organ, though, meaning that mice and other animals are not ideal substitutes in toxicity studies. That’s why Rytting and his team test their nanoparticles by injecting and circulating them through freshly donated human placentas.
These studies are thus limited by the generosity of new mothers, but working with human placentas is also a leaky, messy affair. Chemist Peter Ertl of the Austrian Institute of Technology is developing a placenta-on-a-chip to circumvent this problem.
Ertl’s three-dimensional microfluidic chip is compartmentalized to represent both sides of the placenta: maternal and fetal. Cultured human trophoblast cells separate the compartments. The lab-on-a-chip design allows Ertl and his team to monitor the impact of drugs or engineered nanoparticles on placental cells using electronic and optical diagnostics. The biggest challenge now, he says, is reproducibly generating placental tissue within the chip that structurally and functionally resembles the natural organ.
Both Ertl and Rytting became fathers near the time their careers ventured into placenta research. Because of this, both acknowledge a personal connection with their work that might not be shared by many. But Ertl still seems surprised by the lack of interest in the placenta, especially from the organ-on-a-chip community, where there is greater interest in developing systems to study brains or lungs (see page 19). “The placenta barrier is largely overlooked,” he says. “People say, ‘That’s a nice issue, but it’s not the big issue.’ ”
Saade, who has been treating high-risk pregnancies for nearly three decades, says the lack of interest isn’t limited to the lab-on-a-chip field. Because pregnancy is healthy and normal, most people tend to ignore it in favor of diseases. That’s why, in 2014, humans know so little about an organ critical to the process that perpetuates their existence.
But Saade is hopeful that the Human Placenta Project will change that, not just by calling public attention to the issue, but by attracting researchers who never thought of looking into the science of pregnancy before. “I think it’s like when Kennedy called for America to go to the moon,” he says. “It’s a revolutionary step.”