October 2002

Fetal Fortunes

Continued from page 1

By Jon Cohen

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Although studies have proven that chromosomal abnormalities in offspring become more prevalent as a woman ages, researchers have widely varying estimates of how frequently errors occur. Santiago Munn and colleagues at the Institute for Reproductive Medicine and Science of Saint Barnabas in Livingston, NJ, have shown that up to 70 percent of embryos produced in their clinic for in vitro fertilization-typically for older women with fertility problems-have chromosomal abnormalities that would likely prevent them from properly implanting. But traditional preimplantation genetic diagnosis techniques have failed to have a dramatic impact on success rates.

Comparative genomic hybridization-the technique that worked for Leeanda Wilton in Melbourne-could change that. A shortcoming of standard preimplantation testing is that it can analyze only a handful of chromosomes from each embryo. Wilton and coworkers have shown that analyzing all of an embryo's chromosomes with comparative genomic hybridization detects 75 percent more errors.

Originally developed to detect abnormal amounts of DNA in cancer cells, comparative genomic hybridization compares the number of chromosomes in an embryonic and a normal cell. Researchers remove a single cell from an embryo, labeling its chromosomes with a green fluorescent tag and attach a red fluorescent tag to the chromosomes taken from the normal cell. Next, researchers add both the green and red chromosomes to a set of chromosomes on a glass slide, where they bind to complementary sequences. Software analyzes the fluorescent signals (see "Comparative Genomic Hybridization," below). If the embryo is healthy, each set of reference chromosomes should have an equal amount of red and green. If there's more red than green in, say, chromosome 14, it indicates that the embryo is missing a copy of that chromosome and likely will fail to implant.

Comparative Genomic Hybridization

Detecting for chromosomal defects, researchers label DNA from an embryo with a green tag, and DNA from a normal cell with a red tag. Both are added to a slide, where they compete in binding to template DNA. The high ratio of red to green indicates a missing copy of chromosome 14.

But in addition to simply looking at numbers of chromosomes, preimplantation genetic diagnosis techniques can look for specific genes. This involves using DNA probes designed to marry themselves to parts of a given gene. In 1999 Yury Verlinsky, who directs the Reproductive Genetics Institute in Chicago, used this technique to help a woman undergoing in vitro fertilization select an embryo that did not have the gene for a heritable life-threatening blood disease. An international uproar ensued because the parents also picked an embryo that had the same immune system genes as their daughter, who was five years old at the time and had the disease. The parents hoped that doctors could safely transfer stem cells-which have the ability to differentiate into any type of cell in the body-harvested from the umbilical cord of their newborn to help their ailing daughter. A baby was born in 2000, stem cells were transfused and the older sibling is doing well.

Verlinsky, who has strongly defended the ethics of this intervention, argues that qualms about such genetic diagnoses will subside as the technique continues its inexorable progress from cases of concerned parents who carry known disease genes to those of parents with no known genetic-risk factors but who have difficulty conceiving a baby. "It will probably become routine in all in vitro fertilization cycles," he predicts. It would offer women the option of discarding embryos that have genetic or chromosomal defects. "It's the only scientific proven way to select an embryo. Everything else is absolutely irrelevant."