Tipping points in human ARTs: an opportunity to reconsider the past as a pathway to the future

“A scientist is never certain. We all know that. We know that all our statements are approximate statements with different degrees of certainty; that when a statement is made, the question is not whether it is true or false but rather how likely it is to be true or false. “

Richard Feynman from Ode to a flower: https://www.brainpickings.org/2012/08/27/richard-feynman-on-the-role-of-scientific-culture-in-modern-society/

We begin 2023 with a focus on aspects of male fertility standing not at extremes of certainties, but as Feynman suggests, somewhere with the likelihood of what we are to share with colleagues and patients is in the search for truthiness.

For reproductive scientists and clinicians, the launching of development upon fertilization has come to be appreciated as much more than a matter of a sessile oocyte encountering a hyperactivated sperm poised to charge and discharge its intended cargoes. The respective course of differentiation for both male and female gametes leading up to fertilization is now recognized to involve much more than the information stored within genomes, and as we will see below, more reasons have surfaced to ponder what it is about the history of spermatogenesis that enables spatial and temporal contributions to embryogenesis, so much so that even the ardent oologists among us may have to accept revising the adage:

Embryogenesis begins with oogenesis (and maybe spermatogenesis)

The field of EvoDevo is now asking questions about gametes and embryos that could and should be on the minds of those of us committed to understanding the causes of human infertility and how to best circumvent or ameliorate the complexities of human reproductive physiology tainted by environmental and aging factors that have entered the business of ARTs. From the sperm perspective, the remarkable nano-machine known as the flagellar axoneme captured the attention and experimental resolve of scientists who teased apart piece by piece not only the mechanisms of motility for sperm but the much wider implications for a number of human diseases such as the ciliopathies like Kartagener’s syndrome [1]. How ironic it is to reflect on the use of ICSI enabling many a Kartagener’s patient to pass along their genetic disabilities to male offspring! In the end, matters of motility still constitute a major determinant of male factor and the quest for more reliable, reproducible, and refined methods of sperm selection continues.

Aitken and colleagues report in this issue a multicenter study comparing standard density gradient centrifugation with one of a newer range of methods being tested for clinical sperm selection (A comparison between the Felix™ electrophoretic system of sperm isolation and conventional density gradient centrifugation: a multicentre analysis, 10.1007/s10815-022–02680). And according to a recent bibliographic analysis of research papers in the area of male infertility and ARTs, density gradient centrifugation and ICSI, not surprisingly, rank highly across the publication landscape as most highly studied areas with azoospermia topping clinical reports whereas the field continues to rely upon pregnancy rate for outcome reporting, possibly due to the time the analysis was conducted and published [2]. It is interesting to note that among the sperm contributions to the zygote, besides the genome, that of paternal centriole inheritance has endured a 3-decade-long dogma that would appear to have withstood the “test of time.” Or has it?

Over in one corner of the male infertility domain has been over the years a proffering of speculation about just how neat and clearcut must be the duplication of centrioles during that first zygotic cell cycle such that each and every blastomere would have received its correct numerical endowment to support development from 1-cell to 32-cell and beyond; the 2, 4, 8, 16, 32 magic that assures such symmetry and cadence is the norm rather than the exception. Along comes sperm centriole biologist Tomer Avidor-Reiss.

Avidor-Reiss’ approach is to evaluate subtleties in the design and function of sperm centrioles across species and realizing that variations on the paired centriole at the heart of traditional centrosomes are far more common than previously appreciated [3]. That these so-called atypical centrioles function in human embryos [4] has more recently been followed by further work linking a variety of processing defects now considered to be one of the underlying causes of miscarriage [5]. This comes as no surprise given the robust body of literature over the past few years documenting the widespread nature of cell division abnormalities contributing to embryo arrest, cleavage abnormalities, and failure to form blastocysts in patients across a spectrum of ages.

What is emerging in the field of ARTs is a not so gradual challenge to many of the most fundamental principles that have guided clinical platforms to the point we are now at. Carrying preconceptions or biases into current practice patterns and strategies can only serve to close the door on opportunities that could have been discoveries of the kind made by Avidor-Reiss contextualized by a community of embryologists willing to resist the marketing forces at work currently in ARTs.

Whether rooted in the clinical needs for reliable sperm selection, founded on contemporary knowledge of the link between centrioles and axoneme, or in tracing back to the origins of the unique design principles deployed by sperm over an evolutionary spectrum [6], recognizing the time and place for a tipping point to take place will only enhance our professional and patient outcomes if we are willing to accept the uncertainties upon which we act.

As we start 2023, it is our pleasure to acknowledge members of the Editorial Board whose terms of service have come to an end. Thank you to Ronit Abir, Akwasi Amoaka, Debbie Blake, and Jim Segars. The New Year is also an opportunity to enrich the expertise and commitment of new board members, and it is our pleasure to welcome Dean Morbeck and Paul Pirtea as section editors as well as Michelle Bayefsky, Daniela Bebbere, Howard Cabral, Lynda Harris, Shu Hashimoto, Valentina Lodde, Winifred Mak, Daniela Nogueira, Anna Sokalska, and Elena Yanushpolsky to the Editorial Board.

Finally, to our readership, be on the lookout for a special focus issue on Artificial Intelligence scheduled for next month, our second in a series to update and extend the impact of this technology in the fields of ART and Genetics.