The genomic revolution changing the face of infertility

Going back to the earliest artwork and texts in history, humans have been fascinated with infertility. Old legends and myths tell stories of miraculous births. Hippocrates wrote of infertility, and instead of attributing the issue to magic, he strove to understand the anatomy and even began to formulate treatment options. When von Leeuwenhoek invented the microscope, and then in 1677 discovered sperm, a more modern understanding of infertility started to emerge. Soon, we began to understand cells and then organ systems, and we medically and surgically had our first success stories in treating and curing infertility. By the 1980s, the era of endoscopic surgery on the uterus and fallopian tubes had emerged.

In 1978, doctors Patrick Steptoe and Robert Edwards would change everything, and the first in vitro fertilization (IVF) baby, Louise Brown, was born. Millions of IVF births later, we began to face new problems and find new opportunities. All too often, in an attempt to increase pregnancy success rates, multiple embryos were being transferred, resulting in twins and even triplets. These multiple pregnancies frequently put both mom and the babies at risk.

We needed a way to identify the single best embryo for transfer to maximize the chance of a healthy pregnancy and minimize the possibility of a failed cycle, a miscarriage, or an unhealthy pregnancy. We began to realize that the physical appearance of an embryo is not the only predictor of its viability. Two identical looking embryos might produce very different outcomes if one of them carries genetic abnormalities. So, we needed a way to reliably and affordably test their genomic makeup to ensure that we only transferred the embryos with the best chance of success.

The genomic revolution now allows us to biopsy just a few cells from a blastocyst (early embryo) and get tens of thousands of points of information on every single chromosome, and nearly a million points of data on each embryo. Now we can tell whether the embryo is chromosomally normal or abnormal: Whether it is “euploid,” and contains 46 chromosomes, or “aneuploid” due to monosomy or trisomy of a chromosome or chromosomes. Today’s analytics are so sophisticated that we can even tell if small pieces of DNA are duplicated or deleted (segmental aneuploidy). We have now progressed from the organ to the cell to the subcellular to the genomic, and we’re able to identify the healthiest embryo. I think that this scientific progress is going to continue, and that it is going to continue to improve outcomes, as well as raise ethical issues, of which we must be both aware and respectful.

The next chapter in the genomic story will, I believe, open with whole exome sequencing and transition into whole genome and transcriptome sequencing. We’re going to pick up microdeletions and microduplications, and maybe no longer need genomic-based prenatal testing or chorionic villus sampling. I think that we are likely to be using gene panels to figure out whether an embryo is predisposed to become a child with early childhood cancer. It certainly is likely that, over the next few years, we will be able to use these technologies to prevent more and more diseases.

Another path to preventing disease may be the use of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), which has captured my imagination recently. Instead of just diagnosing a patient or an embryo which is at risk of being unhealthy, what if we could take it that extra mile and fix something before it’s broken? Indeed, CRISPR has already been used to fix disease genes in viable human embryos, although these modified embryos were not allowed to develop beyond an early stage. The science of DNA editing is still in its infancy, but I can imagine a future where we could tell a pancreatic cell to make insulin just by repairing a broken gene or help a couple that is at risk of not being able to have a healthy baby for a variety of reasons. You can also see how DNA editing could stop a baby from expressing certain diseases. Another technique, mitochondrial replacement therapy, has already been approved in the UK. By replacing defective mitochondrial DNA (mtDNA) with healthy mtDNA from a donor egg, it may be possible to prevent babies from inheriting severe metabolic disorders. This year, we can routinely screen embryos with next-generation sequencing. Next year, perhaps we might be able to routinely fix an embryo.

Addressing the ethics accompanying these advances is, of course, of paramount importance. For the first time, humans can change the germline, and we can potentially alter evolution. The power of this technology is massive, but our responsibility, therefore, is also great. Groups that are doing groundbreaking research in this area need to have bioethicists as part of their team, and patients must always be informed.

I think that scientifically, within the next two to three years, we’re going to be able to rank an embryo and not just ask whether it is morphologically attractive and if it has 46 chromosomes. We will also learn about its implantation potential, and possibly even about the health and wellness of the future individual – an ethical slippery slope. Every one of these decisions is loaded – what to test for, how to test, and how to counsel a patient – and we must have deep information about the accuracy, precision, and potential consequences of using such information. I could foresee a future in which testing and embryo selection decisions are made with the patient and the reproductive endocrinologist, as well as the geneticist, the data scientist, and maybe even the bioethicist. The data scientist is crucial as informatics has massive potential to revolutionize fertility outcomes and will usher in the next, post-genomic stage in the evolution of reproductive medicine – a topic I will explore further in my next post.


Alan B. Copperman, M.D.
Chief Medical Officer