How NGS is changing the future of IVF

pharmaphorum interviewed the University of Oxford's Dr Dagan Wells following his recent acknowledgement for his work in using next-generation sequencing (NGS) in the area of reproductive medicine.

Fertility problems are estimated to affect one in sex or one in seven couples in the UK – approximately 3.5 million people. In 2011, over 48,000 women had IVF, according to the Human Fertilisation Embryology Authority (HFEA). However, the success rate of in vitro fertilization (IVF) depends on the age of the woman undergoing treatment, and also on the cause of the infertility (if it's known).

Today, next generation sequencing (NGS) is revolutionising genetic research and diagnostics, especially in the area of reproductive medicine.

The European Society of Human Reproduction and Embryology (ESHRE) recently acknowledged Dr Dagan Wells for his work in this area. Alongside a team of experts, including Drs Jamie Grifo, Michael Glassner and Santiago Munné, Dr Wells worked on a unique and impressive science of genetic derived human embryos to help with the first healthy birth of a baby boy via IVF through NGS.

pharmaphorum's Hannah Blake was honoured to catch up with Dr Wells, who currently works at the NIHR Biomedical Research Centre at the University of Oxford and also at Reprogenetics UK. Dr Wells shared with us his thoughts on how the cost of NGS is significantly lower than that of existing screening methods and how this will affect patients going through IVF in the future.

Interview summary

HB: Thanks for taking part in this interview, Dr Wells. To start, can you tell us a bit about your medical background and your current role please?

DW: My background is in genetics. I studied at University College London and have been on the faculty of both Yale University and the University of Oxford. I have been working closely with Reprogenetics, one of the world's largest providers of preimplantation genetic diagnosis, for more than a decade. It's a fascinating area to work in. Not only does our research shed light on some of the most fundamental aspects of human biology, but it also provides clinically useful information, providing many childless couples with the possibility of being able to start a family. We are passionate about the service we provide and are constantly seeking new ways to make infertility treatments more successful.

"...it also provides clinically useful information, providing many childless couples with the possibility of being able to start a family..."

HB: How did you get involved in genetic diagnostics and the study of fertility?

DW: I wish I could claim that I had foreseen the future and realised what an exciting and worthwhile field of medicine reproductive genetics would become. However, the reality is that I was simply in the right place at the right time. I had the good fortune to find myself in one of the laboratories that pioneered the testing of embryos for serious inherited disorders, the laboratory of Professor Joy Delhanty at University College London. This provided me with an opportunity to participate in some of the first ever cases of genetic diagnosis carried out on embryos, allowing couples at high-risk of passing on catastrophic disorders to have healthy babies, without them ever having to consider pregnancy termination. I was only 21 years old when I carried out my first diagnoses and the children who were born following those cases will be turning 21 themselves in the next few months.

HB: You recently hit the headlines for leading the international research team who developed a new embryo screening approach, preimplantation genetic screening (PGS) – and the first baby born using this technique was just born in the USA. Can you tell us a bit about this project?

DW: It is becoming increasingly clear that one of the main reasons why IVF treatment is unsuccessful is that many of the embryos produced have a problem that prevents them from developing into a fetus. The problem is that they have the wrong number of chromosomes. Chromosomes are microscopic structures found in almost every cell of the body. They are made of a mixture of DNA and proteins and this is where the genes are located. There should be exactly 46 chromosomes, but many embryos have either too many or too few. Such an abnormality is not compatible with life and the affected embryos usually fail to implant in the mother's uterus or miscarry. Tests developed by laboratories like Reprogenetics have allowed us to test embryos produced by IVF and make sure that the ones transferred to the mother have the correct number of chromosomes. This can improve the chances of a pregnancy after infertility treatment and reduce the risk of miscarriage. However, the tests we currently have are quite expensive and not all patients can afford it. We wanted to find a way in which we could bring down the costs of chromosome testing. Our research harnessed a new, powerful technology, called next-generation sequencing, allowing us to count the number of chromosomes in cells from embryos, which in the future, will be less expensive.

"...one of the main reasons why IVF treatment is unsuccessful is that many of the embryos produced have a problem that prevents them from developing..."

HB: How did you feel when the project was successful?

DW: The whole team was delighted by the success of the project. Not only was the scientific and technical achievement a cause for celebration, but the ultimate outcome, helping a really nice couple to start a family, was really rewarding.

HB: How does PGS compare with existing screening methods?

DW: In all IVF clinics around the world, the main way that embryos are chosen for transfer to the mother is just based on their appearance. Unfortunately, the lethal chromosome problems that affect so many of them are invisible to this type of assessment.

HB: In what way is NGS revolutionising genetic research and diagnostics?

DW: NGS is an extremely powerful technology that allows vast quantities of genetic information to be obtained at relatively low cost. The first human genome to be sequenced cost over US $2.5 billion, while using NGS methods a genome can be sequenced for under $5,000.

HB: What are the benefits of this unique PGS technique, not only for people wanting to have a baby, but also to the healthcare system?

DW: Chromosome screening has the potential to reduce the number of IVF treatments needed to produce a baby, reduce the risk of miscarriage and avoid Down syndrome. These aspects of PGS could lead to huge savings for patients, insurers and healthcare systems.

"Chromosome screening has the potential to reduce the number of IVF treatments needed to produce a baby, reduce the risk of miscarriage and avoid Down syndrome."

HB: How can geneticists overcome the challenges that the ever-increasing pace of NGS presents, such as data processing, storage and sequencing quality control?

DW: NGS needs to be undertaken in well-regulated laboratories, run by highly trained staff. The data produced can be of a potentially sensitive nature and consequently it has to be treated with respect and stored safely and privately. It is important to note that although NGS has the capacity to reveal minute detail about the genetic make-up of an individual, in the case of PGS method that Reprogenetics uses, individual genes are not sequenced. We do not learn anything about the characteristics of the embryos tested other than the number of chromosomes in their cells.

HB: What further advancements with NGS do you see happening / want to see happen in the future?

DW: PGS significantly improves the chances of a successful IVF treatment, but even when we transfer an embryo that looks perfect under the microscope, and has the correct normal of chromosomes, we still cannot 100% guarantee a pregnancy. We hope that NGS might help us understand what else can go wrong, preventing an embryo from making a baby.

About the interviewee:

Dr Dagan Wells works at the NIHR Biomedical Research Centre at the University of Oxford, as well as at Reprogenetics UK and Reprogenetics LLC.

Dr Wells studied at University College London (UCL), obtaining bachelors and doctoral degrees in Genetics. He has been actively involved in preimplantation genetic diagnosis (PGD) and the study of human gametes and embryos for two decades, conducting his first PGD cases in 1992.

After a time spent supervising molecular diagnostics at the UCL Centre for PGD in London, Dr Wells moved to the United States and joined Reprogenetics, one of the largest providers of PGD services in the USA. In 2003, he initiated Reprogenetics' highly successful single gene PGD program, testing embryos for numerous serious inherited conditions.

Dr Wells later joined the faculty of Yale University Medical School, where he spent four years as an Assistant Professor, before returning to the UK in October 2007. His research group is now located in the Nuffield Department of Obstetrics and Gynaecology at the University of Oxford and focused on increasing understanding of the molecular genetic processes underlying gametogenesis and preimplantation development.

Where do you see NGS in the area of reproductive medicine advancing in the future?