Unveiling Fetal Development by Use of “Omics”

As molecular technologies advance, scientists are attempting to use “omics” to shed light on critical steps related to fetal development. This work focuses not only on what genes are present and potentially important for fetal and placental development but also when during development these genes play a critical role and how these genes interact with the environment. Simultaneously, clinical genetic technologies continue to evolve, moving from diagnostic testing of amniotic or placental samples to noninvasive screening of placental DNA found in maternal blood. Ainsworth recently highlighted that as these mysteries of development are uncovered, complex questions arise about the ethics of prenatal diagnosis and screening, as well as about emerging possibilities for fetal intervention and therapies to improve clinical outcomes (1).

Next-generation sequencing of whole genomes or exomes (the 1%–2% of the genome that codes for proteins) has greatly advanced our understanding of human development. By focusing on sequencing the DNA from pregnancies with a lethal fetal diagnosis, whole-exome sequencing can discover new genes that are critical to human development (2). Further, by combining this technology with the knowledge that placental DNA is present in the maternal circulation during pregnancy, it is possible to evaluate fetal genomes or exomes without performing any invasive diagnostic procedures (amniocentesis or chorionic villus sampling) to obtain a DNA sample representative of the fetus.

Although DNA may provide the “why” by noting what change in the genetic code is responsible for a birth defect, it is not always sufficient to provide the “how.” By focusing on the RNA molecule, which is responsible for taking the message from the DNA instructions and turning these instructions into a functional protein, researchers are trying to solve this puzzle. This research focuses on the fetal transcriptome (RNA output) to determine what genes are critical at which point in human development. Diana Bianchi, Director of the National Institute of Child Health and Development, is exploring how the fetal transcriptome differs between typical fetuses and fetuses with Down syndrome. Her work has shown that fetuses with Down syndrome may be more vulnerable to oxidative stress than those without Down syndrome, and her group is currently using mouse models to explore possible fetal interventions to protect against fetal damage from oxidative stress and improve outcomes.

Newer technologies are allowing for a more advanced interrogation of the transcriptome by using RNA-seq to fully determine the RNA profile. Much like DNA sequencing, this technology is now being explored using maternal blood to determine how the placental RNA profile changes throughout gestation and with certain maternal diseases, such as preeclampsia, or environmental exposures, such as smoking.

As we gain the ability to fully examine the fetal exome, genome, and transcriptome, ethical challenges will surely follow. It will be critical that implementation of any clinical testing by using these technologies includes a thorough informed consent process, as these tests can identify changes in both maternal and fetal DNA that may predict an increased risk of adult-onset conditions later in life (such as breast cancer) or identify DNA variants that may not be well understood. Surely, as these technologies continue to provide more answers, they will equally lead to more questions.