Rajiv McCoy, an assistant professor in the Department of Biology, and his collaborators at London Women’s Clinic in the U.K. discovered a strong correlation between chromosome abnormalities, embryo arrest and low blastocyst morphological grading of the in vitro fertilization (IVF) of human preimplantation embryos. Their results were recently published in Genome Medicine.
McCoy’s lab utilizes computational and statistical approaches to study the human genome and how it provides insight into human evolution and human reproduction. One of their focuses is investigating the origin of chromosomal abnormalities in early human development.
Aneuploidy, which means abnormal chromosome gains and losses, is understood as an important reason behind pregnancy loss in humans. Aneuploidy can either happen before fertilization in the formation of sperm or egg, or during initial cell divisions of the embryo after fertilization. In addition to natural pregnancies, aneuploidy can affect outcomes of IVF.
IVF embryos are often used to study how chromosomal abnormalities contribute to early embryo development. Many studies in this field only examine IVF embryos that survive and meet the criteria for transfer into the uterus.
The research team recognized the limitation of this method in previous studies.
“The problem with [only studying embryos that were tested in clinics] is that it introduces biases into the data. Only embryos that actually survive to the point that they would be tested end up in the data, and half of embryos in IVF stop developing after just a couple of days of development,” McCoy said in an interview with The News-Letter.
Therefore, McCoy’s team had to study embryos that fail to survive until the time of testing or fail to satisfy their IVF candidacy since they provide more insights into the connection between chromosomal abnormalities and early embryo development.
In this project, the Hopkins team collaborated with London Women’s Clinic where clinical data was first collected. McCoy’s lab was brought on the team for computational and statistical expertise in data analysis. Genetic testing from biopsies and real-time monitoring of cell division through time lapse were employed to identify the possible contribution of cell division and chromosome abnormalities to IVF outcome in the first few days of embryo development.
During the course of IVF treatment, embryologists fertilize the egg and sperm collected from patients in vitro, in a culture dish. On the fifth day after fertilization, the embryologists evaluate the embryo morphology with two letter grades. Blastocyst morphological grading is used to which evaluate an embryo’s quality and its potential to result in healthy live birth. One letter grade is given for the inner cell mass, which is the part of the embryo that will become the fetus. The other letter grade is given for the trophectoderm, which is an outer cell layer that will become the placenta.
McCoy and his team found a strong correlation between the embryo quality indicated by the letter grades and occurrence of aneuploidy. Arrested embryos showed the highest incidence of aneuploidy.
McCoy said that their results will have strong significance in human developmental biology, specifically the origin of chromosomal aneuploidy. Their findings can also have important implications for both natural conception and IVF. Aneuploidy could be one of the factors that lead to implantation failure.
The utilization of IVF embryos in the study also raises questions as to what extent the aneuploidy could be an artifact of IVF. For example, the chemical composition of the culture media in which IVF embryos are grown could have an effect on patterns of abnormal cell division and aneuploidy that does not apply for natural pregnancies.
Looking ahead, McCoy wants to use higher resolution methods to study individual cells in an embryo. This study was based on biopsies of multiple cells in an embryo or an entire embryo. However, some cells in the biopsy may be completely chromosomally normal, but the biopsy results may identify them as abnormal due to the presence of other cells with aneuploidy.
McCoy shared his vision for future directions of research.
“It’s been a question in the field of preimplantation genetic testing: What do you do with [embryos with aneuploidy affecting only a subset of cells or only a portion of a chromosome]? Should those embryos be transferred? We are trying to leverage data from human genetics — for example, population data from living individuals — to understand which forms of chromosome abnormality are viable, which ones are harmful and which ones are lethal,” McCoy said.
