What we have here is a failure to fertilize: back to basics.

Despite all efforts taken in the ART laboratory to make the dialogue between egg and sperm fulfilling as a means to embryo production, failure to fertilize continues to be an obstacle thwarting the hopes of many patients in their quest of parenthood. Even the introduction of ICSI some 20 years ago, while measurably improving the efficiency of egg activation and embryo production, remains inadequate in a minority of cases at effecting the signaling pathways that we now appreciate are the hallmarks of human fertilization. ICSI itself has evolved over the years as a means for dealing with many of the most challenging cases of male infertility—from tree-trimming the flagellum to taking the role of PLCζ out of the “hands” of the already deconstructed spermatozoon by spiking injection medium with calcium—all modifications of the original procedures that derived from a solid foundation in reductionistic basic science. But even the injection pipette with its cell (castrated as it is) and ionic contents remain incompetent to fertilize some eggs. Why? Our issue of JARG this month features conundrums of fertilization with immediate clinical implications. And, in what we are sometimes able to remind our readership of, the mechanisms underscoring male infertility and fertilization failure have overlooked a historical framework that is often clouded in importance and worthy of reinterpretation in light of recent findings. Begin with our cover this month. Tracing over a century’s worth of discovery, this montage displays both the familiar (outer edges) and hidden (center) underpinnings of the sperm tail or flagellum with which the male gamete obtains its ticket to ride towards destiny. Among the many microtubules that comprise the axonemal cytoskeleton is a subclass of biochemically unique filaments made of subunits of proteins known as tektins—the fine filaments shown on the cover. Tektins became suspect in being prime movers of human sperm in a paper published in JARG just over 2 years ago with increased levels of this protein associated with improved fertilization rates and embryo quality (Bhilawadikar et al., JARG 2013, 30:513–523, DOI 10.1007/s10815-013-9972-6). For more on tektins and axonemal motility, we ask our readers to look out for detailed coverage of this topic in an upcoming issue. For the “failed fertilization” fans among you, you need not look any further than what lies ahead. From sperm tail proteomics, to a mutational analysis of sperm motility, to matters well in excess of the predictable and oft implicated PLC zeta sparking during egg activation, a collection of thought-provoking papers that touch upon various aspects of the enigma of human fertilization lead of this issue. For more suspicion and intrigue, take a close look at the contributions by Vassena and colleagues whose results highlight that even in cases of proven male fertility, molecular players other than those typically involved in egg activation Capsule Despite a deepening understanding of the molecular underpinnings of fertilization in humans, the processes that launch the earliest steps in the pathway to embryogenesis continue to elude management and explanation for the many patients awaiting good news the day after egg retrieval. This issue of JARG brings to surface some of the more fundamental aspects of egg activation empowered by the motility properties of sperm that offer clinically tractable solutions to the problem of fertilization failure.