Failure to focus seems to be a hominid thing

Research over the last 70 years in reproductive biology and medicine has formed the basis for human ARTs as practiced today. But just how many of us have even a remote sense for just how the origins of our field were taking form long before Edwards and Steptoe undertook their valiant charge leading to the birth of Louise Brown in the summer of 1978. Bob Edwards often drew attention to his humble beginnings as a geneticist whose original curiosity aimed to understand the “dance of the chromosomes” during meiosis in mammalian oocytes long before we fully appreciated just how precarious the process of aligning and segregating bivalents was and how it would play into our understanding of the origins and impact of aneuploidy during early human development. More on the matter of focus and the dynamics of chromosome behavior on the meiotic spindle below.

But before we return to the subject of dancing chromosomes and the proclivities and odd tendencies we hominids demonstrate during such pivotal stages of early development, this month we reflect back to a much overlooked history of the science that shaped the present focus, at least through the lens of someone who had the privilege of training during the 1970s.

As noted in our focus issue on oocyte in vitro maturation in June of 2021, the early days of reproductive medicine had little to do with diagnosing or managing infertility. Yet to be understood were fundamental principles of mammalian gamete differentiation, fertilization, and embryogenesis as well as the core elements of reproductive physiology that today, we take for granted as ancillary, but telling, indicators of how well we did prior to oocyte retrieval or following embryo transfer. The names of Pincus and Rock resonate to this day given their contributions in synergizing basic science with, in their time, development of the birth control pill. Why? Because the focus was on population control and achieving some form of gender equality-hence the name of game at that time was CONTRACEPTION, a goal only achievable with a solid foundation of reproductive biology.

During my tenure as EiC of JARG, and admitting my dinosaurian status in this field, it has become clear to me, and perhaps others, that reproductive medicine today has lost focus with respect to its roots. Moreover, rather than acknowledging this historical backdrop, today’s specialists appear to find solace, “truth” and direction in a literature base hardly even a decade old. As leaders of that great era of the 1960s and 1970s pass on, it is but one hope for JARG to reacquaint our readership with those who truly made a difference in the evolution of reproductive medicine to what it is today.

The recent passing of Sir David T. Baird of Edinburgh has given many a physician and scientist pause to reflect on his life and how it exemplifies the loss of focus in our discipline. We will in the future provide our readership with a more thorough and complete coverage recognizing this giant in the field of reproductive medicine but in the moment trace events of the earliest stages of his career to something tangible and current in today’s world (https://www.scotsman.com/news/people/obituary-david-baird-world-expert-in-reproductive-biology-3592882).

David’s primordial research experience, following medical training in Edinburgh, was enabled by his receipt of an MRC fellowship that in 1965 delivered him to the hallowed grounds of the Worcester Foundation for Experimental Biology (WFEB) located in Shrewsbury Massachusetts. There, in collaboration with fellow Scotsman John McCracken, his pioneering research established the sheep ovarian autologous transplantation model with which the physiology of the ovine estrous cycle was established- a forerunner of Baird’s many contributions to human ovarian function leading eventually to the refinement of ovarian and uterine transplant approaches constituting so much of the current day fertility preservation strategies [1].

That the seeds of such a prolific and influential career were sown in the WFEB environs was chance (in the Pasteurian sense) only because he worked with and around those responsible for building the foundation upon which reproductive medicine rests firmly today. The names of Pincus, Chang, and Rock immediately come to mind but in recognition of Women’s History Month, how fitting it is to remember the seminal contributions of Miriam Menkin in conducting the first reported case of IVF in humans (https://www.bbc.com/future/article/20200103-the-female-scientist-who-changed-human-fertility-forever).

Let’s return to the dancing chromosomes.

There was a time when most errors in chromosome segregation were ascribed to be of meiotic origin. But recent discoveries into the depths of embryogenesis in mammals now suggests that while the road to the completion of meiosis may indeed be a treacherous one -and causative on the way to aneuploidy in the conceptus [2], the zygote’s attempts to switch from meiosis to mitosis is equally suspect as a condition leading to genomic imbalances with both short term consequences, like embryo arrest, and potentially some impacting health status in adulthood [3].

How Bob Edwards would have reacted to recent revelations of the “dance” in stepwise movements in, about, and on the dancefloor- the meiotic spindle- is anyone’s guess. But astonishment comes to mind as an apt descriptor. This was first revealed in the elegant studies of Holubcova and colleagues back in 2015 through a what has become a fruitful collaboration between the laboratories of Kay Elder and Melina Schuh [4]. If you have yet to witness the data in this paper, do so soon to get a better sense for just how chaotic the “dance” is in human oocytes. That work (live imaging movies) draws immediate attention to the repeated excursions bivalents exhibited, setting the stage for examining the molecular underpinnings for seemingly erratic dancing, prompting the publication of their latest study. And back to the matter of focus, the most recent work now demonstrates that the forces focusing the poles of the meiotic spindle in part explain the risky behavior of chromosome segregation in human oocytes, a property of the final stages of meiosis setting us apart from the behaviors exhibited by other mammalian species [5].

On the road to their remarkable discovery, So and colleagues identify a special partnership between the proteins NUMA, a factor known to bundle MT minus end, and the protein KIFC1. In a true example of hypothesis-driven research, they show how the laxity of spindle pole focus in human oocyte can be corrected or rectified by overcoming an inherent deficiency in KIFC1 found in human, but not other mammalian oocytes. Congratulations again to this group of scientists for illuminating such a fundamental dimension of meiotic spindle function and one that is so close to the heart of human infertility.

For example, these reported hominid error-prone behaviors, underscoring at this distal end of the meiosis spectrum, may offer insights into the “age-old” problem of maternal aging at the beginnings where recombination events play a role [6]. Even more intriguing is the recognition that the aging issue stretches across the hominid reproductive lifespan, suggesting that findings like those of So and colleagues may translate into experimentally tractable platforms offering possible clinical interventions somewhere into the future [7].

From focusing spindle poles to tasking ourselves to not overlook the past, we can only hope during these troubled times that the science that has been made possible by the evolution of human ARTs continues to extend a rich history for the benefit of global reproductive health. Be on the lookout for our April issue featuring advances in human ARTs through the lens of The Italian Society of Embryology, Reproduction and Research (SIERR).