In vitro fertilization: From science fiction to reality and beyond

The renowned author Aldous Huxley captured global interest in the potential of laboratory-born babies rather than traditional childbirth with his iconic 1932 science fiction novel “Brave New World.”[1] While some initial progress has been made in this direction, his projections regarding human fertility largely remain within the realm of speculative fiction, eagerly awaiting the eventual realization. The idea of being able to overcome barriers in procreation has roots deep-seated back to 1890—when a British zoologist Walter Heape showed that it was possible to transfer embryos when he put Angora-fertilized eggs into a Belgian Hare doe rabbit, which gave birth to Angora offspring metaphorically an interspecies surrogacy. It was far later than this that the first birth of an in vitro fertilization (IVF) baby was witnessed in 1978. Robert Edwards and Patrick Steptoe published this report in The Lancet titled “Birth after Reimplantation of a Human Embryo.”[2] Since its clinical introduction, IVF has redefined the ability of the human species to procreate. From baby Louis to now 30 years later, about 3 million babies have been born with IVF. Even though IVF benefits infertile couples, about 10% of all the beneficiaries are not restricted to just them. Clinical indications for IVF have rapidly expanded to include medical and genetic conditions and fertility preservation.[3] An additional driver of IVF utilization is the growing societal acceptance of nontraditional families, including single and same-sex parents, and social media that has opened our minds to think beyond the conventional.[4] The Career driven society has the option of oocyte freezing available, which later form healthy embryos defying age bars and has revolutionized the modern concept of fertility assistance. IVF involves a series of steps, including controlled ovarian hyperstimulation, oocyte retrieval, fertilization, embryo culture, embryo selection, and embryo transfer. A significant limitation of this technique is the inability to enhance the quality of obtained oocytes or sperm. In response to this challenge, efforts have been directed toward augmenting the number of collected eggs or sperm.[5] Despite using expert and stringent morphological criteria to choose embryos, only 52.3% of 2.3 transferred embryos typically result in a live birth.[6] This creates a significant 48% margin of uncertainty that proves challenging to surmount, mainly attributed to the absence of techniques for enhancing gamete quality. Furthermore, the uncertain implantation outcome necessitates transferring more embryos to counterbalance this unpredictability. Using multiple embryos during transfer contributes to a significant rate of multiple births, reaching about 30% in patients undergoing assisted reproductive techniques (ARTs). This circumstance adds to the associated perinatal morbidity, resulting in implications such as preterm birth, prolonged stay in the neonatal intensive care unit (NICU), heightened vulnerability to infections, and compromised lung development. IVF involves controlled ovarian hyperstimulation, oocyte retrieval, fertilization, embryo culture, selection, and transfer. The central limitation of this approach lies in our incapacity to enhance the quality of obtained oocytes or sperm. However, this constraint is counterbalanced by increasing the quantity of retrieved eggs or sperm.[5] Despite using expert and stringent morphological criteria for embryo selection, only 52.3% of 2.3 transferred embryos yield a live birth.[6] Given the current lack of means to improve gamete quality, this leaves a substantial 48% margin that is challenging to bridge. Adding to this challenge, the uncertainty surrounding implantation success necessitates transferring more embryos to address this unpredictability. It employs multiple embryos during transfer, resulting in a notable rate of multiple births, reaching approximately 30% in ART patients. This contributes to the morbidity associated with the procedure, leading to significant perinatal implications such as preterm birth, extended stays in the NICU, susceptibility to infections, and compromised lung development. The selection of embryos relies on morphological attributes in conjunction with their developmental progress in culture.[7] Favorable selection criteria encompass factors like the blastomere count, absence of multinucleation, early cleavage to the two-cell stage, and a minimal proportion of cell fragments within embryos. The state of blastocoelic cavity expansion and the cohesion and count of inner cell mass and trophectodermal cells is pivotal in determining implantation and pregnancy rates. This traditional assessment, conducted by embryologists and clinical fertility experts, is on the brink of being replaced by an artificial intelligence (AI)-based sequential embryo evaluation model coupled with a computer algorithm for precise morphological embryo selection.[8-10] Furthermore, relying solely on the morphological assessment of embryos introduces room for error. To tackle this challenge, the incorporation of metabolomic profiling into the culture media of embryos has been adopted, utilizing proton nuclear magnetic resonance (1H NMR). The metabolomics profile exhibited a correlation with the reproductive potential of embryos. Analysis of the proton NMR spectrum revealed decreased levels of alanine, pyruvate, and glucose in embryo culture media, leading to successful pregnancies. Elevated levels of glutamate were observed compared with embryos that failed to implant, possibly stemming from its generation via α-ketoglutarate and ammonium, consequently reducing potentially harmful ammonium levels for developing embryos. Using 1H NMR, a sensitivity rate of 88.2% for identifying true implantations/pregnancies and a specificity rate of 88.2% for accurately predicting nonimplantations/pregnancies were achieved. The selection process that was once a “beauty contest,” simply evaluating embryo appearance, will soon include metabolic, protein, and genomic markers as assessment criteria.[11] Microfluidics is a multidisciplinary field of study and design whereby fluid behaviors are accurately controlled and manipulated with small-scale geometric constraints that yield dominance of surface forces over volumetric counterparts. Until yet, microfluidics has also been handled in a macro way: (2) precisely controlled fluidic gamete/embryo manipulations; (3) providing biomimetic environments for culture; (4) facilitating microscale genetic and molecular bioassays; and (5) enabling miniaturization and automation.[11] Adopting automated IVF systems will offer multiple advantages: standardization of workflow, reduction in errors, reduction in cost, reduction in contamination, and the potential for incremental system improvement via machine learning. Another area that has been difficult to manage is the elimination of certain genetic disorders. As carrier screening costs decrease and the number of detected mutations expands, a substantial new population of patients may get identified as carriers and pursue IVF with preimplantation genetic testing (PGT) to build their families. Indeed, population genomic screening of young adults may offer significant healthcare savings by preventing rare disorders and cancers. Future applications of PGT may expand to multifactorial diseases and whole-exome screening. However, current attempts at introducing embryo selection based on polygenic scores into clinical practice seem premature and fraught with ethical challenges. Recent improvements in micromanipulation techniques and the development of CRISPR-Cas9 gene-editing tools raise the prospect of germline genome modification (GGM) for severe monogenic disorders. Indeed, GGM has already been achieved in animal embryos. Mitochondrial replacement therapy for the prevention of heritable mitochondrial DNA diseases is even further developed than GGM, with clinical trials already underway in the UK. Now, even after selecting the best embryo, implantation is not guaranteed. After the advent of customized endometrial receptivity assay (ERA) transfer cycles, the future of the endometrial building will be drugs that actively help in opposition, adhesion, and implantation and imaging techniques that will tell us whether or not the embryos have implanted before measuring the B-hcg, thereby preventing cycles of wasted luteal phase support. Uterus-like dynamic environment with an optimal dynamic amount of oxygen and nutrients will be available externally, making the presumptuous embryo implantation more certain. In the time-lapse machine, we will actively see the embryos growing even beyond the blastocyst stage. A 3-D fetus with a desired genetic composition that eliminates the possibility of hereditary disorders with better intergenerational health, growing in an artificial dynamic womb-like environment—regulated by AI and all of this within ethical bounds—is the fertility future the world awaits. In closing, we wish to extend homage to the illustrious writer Aldous Huxley, whose renowned masterpiece “Brave New World,” penned in 1932, has been the impetus behind this article. We find ourselves drawing closer to his prescient visions of human fertility than ever before. His anticipation of genetic manipulation in human fetuses has transformed into a conceivable prospect through applying the “CRISPR” gene-editing technology, albeit currently restricted to animal models due to ethical constraints. Similarly, the author’s projection of nurturing fetuses external to the womb has achieved notable strides, as evidenced by the advancement of artificial placenta technology. Successful trials involving sheep and piglets have been conducted,[12] with human trials for extremely preterm infants also underway. Today, we witness that the science fiction woven by Aldous Huxley is no longer an implausible distance from actuality. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.