THE CENTER FOR PREIMPLANTATION GENETICS, LABCORP
Embryos whose cells acquire too many or too few chromosomes have a diminished chance of surviving to full term. If they do survive, the abnormal count could result in Down syndrome or another chromosomal disorder. But some of these defective embryos can actually fix their genetic mistakes, according to a study reported last week at the European Society of Human Reproduction and Embryology meeting in Stockholm, Sweden.
The idea was originally proposed in the 1990s, but with little evidence and a lot of skepticism, had quickly fallen by the wayside. The new study garners support for this controversial concept that, if true, is certain to impact patients and doctors involved in the infertility treatment, in vitro fertilization (IVF).
"I think this is an important phenomenon to investigate," says Nathan Treff, a reproductive geneticist at Reproductive Medicine Associates of New Jersey in Morristown. "But," he added, "the strength of the evidence must be higher if we are going to help people have healthy children."
Three days after a woman’s eggs are fertilized in culture, many IVF clinics check to see if the 5 to 8 cells of the embryos have the correct number of chromosomes. If some cells have too few or too many chromosomes, the mother is likely to suffer a miscarriage, and the team may recommend against implanting the embryo.
William Kearns, director of the Shady Grove Center for Preimplantation Genetics in Rockville, Maryland, and his team decided to take advantage of this practice to see if the embryos maintained their genetic defects as they developed. Using SNP microarrays, they reassessed abnormal 3-day-old IVF embryos, which their patients had consented to donate to science, two days later. While only a fraction of these abnormal embryos survived those two days, many that did appeared normal.
“To us, this really changes the paradigm for IVF and genetic testing on embryos because most clinics do a biopsy after 3 days, and decide whether or not to discard the embryo,” said Kearns. “This study says maybe we should freeze those abnormal embryos so that they remain in a viable state until we know what our findings mean.”
But how such a chromosomal correction might occur remains a mystery. Kearns speculates that the abnormal cells die or get pushed aside towards a less vital region, such as the placenta, as normal cells divide to form the three germ layers that give rise to the baby itself. Abnormal cells in the placenta would not necessarily kill the fetus, Kearns said. Indeed, investigators reported in 1983 that a small percentage of placental cells have erroneous chromosome counts , leading others to suggest just such an idea, said Joyce Harper, an reproductive geneticist at University College London.
The mechanism by which an embryo could recognize a genetic abnormality and either kill or actively push these cells to the side, however, is a bit hard to imagine, said Mark Martindale, an embryologist at Kewalo Marine Laboratory in Honolulu, Hawaii. “I assume genetic abnormalities would have to be detected on the cell surface, and I have no idea how that would happen at such an early stage.”
Treff questions the validity of the results altogether. He points to the lack of a control, noting that there’s no way to know how accurately Kearns’ microarray technique assessed chromosome number. Kearns countered that he’s previously validated his technique, adding that researchers simply “don’t have the luxury of using human embryos as controls.”
But Harper thinks the finding is quite likely real. At this point, she said, she’s heard enough presentations about embryos with problems at day 3, which somehow subside by day 5, that clinicians should start taking the hint. “Kearns’s study just confirms what we’ve said for years. Do not genetically test the embryo on day 3,” she said, pointing to a recent clinical trial she led that showed no increase in pregnancy rates by screening embryos at this stage. She says until there’s evidence of a benefit from clinical trials, counting embryos' chromosomes prior to implantation need not be done. “It’s just not fair to patients or the to the IVF team to do time-consuming and expensive procedures for no reason. This is a real bee in my bonnet.”