Competencies and contingencies in the expanding ART marketplace: is there a place for precision medicine

The call for precision medicine has reached all corners of the health care industry both in terms of specialty disciplines and the enabling of an altered landscape of patient care. Perhaps no discipline has embraced the challenge of appreciating and effecting patient care on a precision-based level than that of oncology. We will speak more to this application of precision medicine strategies broadly and to the specific case of oncofertility and fertility preservation below. But in the most immediate matter pertaining to human ARTs, we take aim this month on how our discipline will adapt to the future, and growing needs of patients, as the world of precision medicine transits from conceptualization to practice.

In their recent thought experiment, Alvarez-Dominguez and Melton revisit the question of cell maturation, a notion we have customarily come to think of as a unidirectional process [1]. While focused on the matter of cells as distinct units contributing to the overall homeostasis of an organism, their analysis of how basic concepts in cell differentiation have changed over the years prompts consideration on a broader level as follows. First, it is now recognized that cells within an organ while similar in appearance and composition are not as homogeneous as previously thought in parallel with contemporaneous recognition that the level of heterogeneity between humans, whether speaking of genetic, epigenetic, metabolic, or reproductive competence, far exceeds our long held, and much-outdated, understanding of human biology. What makes this idea attractive as a metaphor for the human condition is the dependence on certain contingencies being fulfilled along the course of a cell’s lifespan in a precise sequence involving commitment to a certain fate, the acquisition of a phenotype unique to that cell, and the eventual loss of that phenotype as the cell ages and dies. This idea finds credence and merit in the context of human reproduction especially as related to the topics of developmental competence acquisition—for oocytes, sperm, and embryos—and the overall problem of reproductive aging.

But, Alvarez-Dominguez and Melton ask us to take a step outside the realm of the unidirectional to consider instead a model of cell maturation whereby various stages need not be fixed sequentially, engaging in their words a “fluid continuum” permissive in the sense that competencies can be acquired or lost due to changes in the environment. For those of us searching for the evidence of such an idea in reproductive medicine, we need not look further than the many examples of how lifestyle patterns alone impact our fecundity.

Traditions in reproductive biology and medicine speak directly to the idea of flexibility first painted in the model of unidirectionality used to explain the gradual acquisition of developmental competencies during oogenesis and early development, pace-setting studies performed on the mouse in the Eppig laboratory [2, 3]. Moreover, the notion of competencies and contingencies at each of the steps involved with gametogenesis and embryogenesis has become part of the ART vernacular and used to explain why what we do sometimes works for producing a baby, but often fails.

With this backdrop, we highlight how the matter of competence continues to play deeply into the biology of gametes and embryos in the realm of human ARTs. In large measure, this is due to the fact that some months ago the leadership of The Italian Society of Embryology, Reproduction, and Research (SIERR) approached JARG with the idea of building this special issue to offer our readership an opportunity to be enlightened on matters of aging and developmental competence. We thank them for their vision and provide herein the series of papers that resulted from this initial query.

Here at JARG, we see such a collection of papers from distinguished researchers as an opportunity to address where we have been as a medical discipline, and what the future might hold. In particular, these contributions establish a timely resource for appreciating the many interconnections between genetics, epigenetics, lifestyle, and environmental factors that will contribute to, and foster a “maturing” perspective on reproductive health and infertility as we move into the era of precision medicine. To do so, at least partially, means confronting the matter of heterogeneity between our patients, and their gametes and embryos.

Implementing precision medicine in human ARTs will not be without its hurdles and challenges. If we take a chapter from the playbook in oncology, what immediately comes to the surface is the complexity beyond the world of genetics when the target is more patient-specific drug targeting invoking the role of epigenetic and environmental factors that together define risks for prevention before it is too late [4]. Organoids are meeting this challenge in the field of cancer [5].

And not surprisingly, the field of fertility preservation within the purview of human ARTs is already on track with both practical and translational efforts that begin to sort out what best course of treatments and outcomes could become available if—and the contingency is substantive here—we take a more fluid stance to future practice patterns [6].

So in returning to the theme of competency, it is useful to bear in mind that while our focus practically involves the gametes and embryos destined for transfer, so much of what and how competence is acquired, manifest, or lost will all come down to keeping an open mind as new technologies reach the ART marketplace [7]. If there is one thing from the recent history of human ARTs exemplifying the consequences of setting our sights too narrow, it is to reflect on the imposition of the various “-omics” alongside progressively longer culture periods, to assay a single parameter of putative importance to the decision-making process of embryo selection. Here we have been decidedly unidirectional and monotoned in our belief that a single measure of something could reflect the complexity of the early conceptus and its likelihood of developing to term. Call it wishful thinking or simply overlooking what other medical disciplines have already appreciated and engaged—the world of “-omics” needs to be one of multiples [8].