Scientific priorities for assisted reproduction in the 21st century

Scientific priorities for assisted reproduction in the 21st century

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When Drs. Robert G. Edwards and Patrick Steptoe successfully fertilized a human egg, grew it briefly in a petri dish, and transferred it into a woman’s uterus to produce a baby, a new era in medicine was begun [1]. This groundbreaking achievement enabled millions of infertile couples to conceive. Consequently, in 2010 Dr. Edwards was awarded the Nobel Prize for physiology/medicine, while Dr. Steptoe, who died in 1988, could not share the award as Nobel prizes are not awarded posthumously.

Not unlike many other pioneers of science, Edwards and Steptoe achieved what they did despite a skeptical establishment and many vocal critics, some of whom believed that the idea of a “test tube baby” was immoral. They could not obtain funding from the government and they had to rely on private sources to conduct their experiments in the small hospital laboratory outside Manchester, United Kingdom, where they delivered the world’s first IVF baby, Louise Brown, on July 25, 1978.

Soon after the first IVF birth came the concepts of controlled ovarian hyperstimulation to generate more than one egg per cycle [2], followed by embryo [3] and oocyte [4] cryopreservation, pre-implantation genetic testing for monogenic disorders (PGT-M) [5,6], and intracytoplasmic sperm injection (ICSI) to overcome fertilization defects [7]. As it was the case for Drs. Edwards and Steptoe, many of the researchers who contributed to these advances in assisted reproductive technologies (ART) relied on private financing and faced heavy criticism from conservative opinion-makers.

Today, encouraged by the rapid advances in the field of assisted reproduction that took place in the past four decades, we dare to predict that the field will continue to evolve, and evolve rapidly. The key questions are: where to go from here and how to pay for the journey? In our attempt to identify worthy targets for future research, we feel the need to revisit our basic mission: to achieve a healthy birth for our patients. Now we know that this can best be accomplished by elective single embryo transfer, therefore urging us to develop approaches that will allow better selection of viable embryos in the setting of ART.

Identifying the viable embryo(s) within the cohort of embryos generated through IVF in a given cycle has long been a research focus for clinicians and embryologists.

Within this context, embryo grading systems based on cleavage rate and morphology were developed and remain the mainstay of embryo assessment and selection in the IVF laboratory [8]. Pre-implantation genetic testing for aneuploidy (PGT-A) [9], transcriptomic analysis of cumulus/granulosa cells [10], and metabolic/metabolomic analysis of spent embryo culture medium [11, 12] have been investigated as potential predictors of embryo viability. However, with the exception of PGT-A [13, 14, 15], these novel technologies have not been proven to be effective in the clinical IVF setting [10, 16-19]. Importantly, despite these advances, and under the best circumstances combining extended culture, PGT-A, and frozen embryo transfer, one third of embryos fail to implant [14]. Therefore, looking for additional biomarkers of embryo viability, whether invasive or non-invasive, seems like a worthy endeavor.

More daring research avenues, many of which are pursued at IVIRMA, include editing the embryonic genome to correct known mutations [20, 21], and introducing donor mitochondria into oocytes to prevent devastating mitochondrial diseases [22]. Particularly interesting are research aimed at allowing older reproductive age women who cannot conceive with current technologies to achieve parenthood by providing cytoplasm from younger oocytes [23], or thorough interventions that rejuvenate aging ovaries [24, 25, 26],

As important as deciding which research question to pursue is how to fund the research project and how to establish the logistics. Indeed, federal funding is often associated with a number of limitations. As an example, in the USA, yearly federal funding for infertility research is approximately 60 million US dollars. While this seems like a large number, when indirect costs (paid to academic institutions), and investigator and trainee salaries are removed, the remaining funding for actual experiments (based on our calculations) is less than 15 million US dollars per year. What is more, investigators are not allowed to experiment on embryos or even oocytes that interacted with sperm, limiting the potential for discoveries relevant to human assisted reproduction. This is where organizations like IVIRMA that are committed to scientific research and willing to channel resources to scientific discovery come into play.

We hope and believe that a collaborative effort between private organizations such as IVIRMA, federal funding agencies such as the National Institute of Child Health and Development (NICHD), and professional societies (such as the American Society for Reproductive Medicine (ASRM) and the European Society for Human Reproduction and Embryology (ESHRE)) will enable us to reach our ambitious goal of enabling each one of our patients reach their dream of parenthood.

Post by Emre Seli, M.D.


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