Personal reflections on Stan Korsmeyer and his continuing impact on our work to delineate the role of Bax in female reproduction

In 1993, the lab of Stan Korsmeyer identified the gene encoding Bax (i.e., Bcl-2-associated X protein),¹ the first proapoptotic member of a now quite expansive and very important gene family.² Bax was isolated by its ability to bind with Bcl-2, the antiapoptotic founding member of this family that was characterized in parallel by a number of laboratories, including Stan's, in the mid-1980s from a chromosomal translocation involved in human lymphoma.^{3, 4, 5} Two years after the discovery of Bax, the results of a gene targeting study conducted in mice by Stan's lab confirmed a central role for Bax in regulating cell death in several tissues, including the male and female gonads.⁶ It was during these initial years of Stan's pioneering work on the genetics of apoptosis that I had the opportunity to become involved in what turned out to be more than a decade of insightful and rewarding collaborative studies with Stan that explored the mechanisms of cell death regulation in the mammalian ovary.⁷ As I now sit here – almost 13 years to the day that I, then a new Assistant Professor fresh out of my Postdoctoral studies, initially contacted Stan with quite a bit of (retrospectively unfounded) trepidation to seek his help – and reflect on the many milestones we reached together along the way, it is clear to me that Stan's premature passing has not diminished the impact of his remarkable vision and his love for scientific discovery on many experiments still ongoing in my lab. As a testament to how this one individual has made such a difference in the lives of those fortunate to have known him, I write this commentary to celebrate Stan's life by highlighting one of many examples of his continuing influence on my work to characterize development and death of the female germline.

The occurrence of cell death in the mammalian ovary was initially described in 1885,⁸ although efforts to understand the roles and regulation of cell death in the female gonads did not begin in earnest until more than a century later. However, after initial corroborating reports that apoptosis was involved in the loss of germ cells contained within follicles^{9, 10} – a normal degenerative process that serves as the driving force behind age-related ovarian failure and the menopause – rapid progress was made through the 1990s in identifying genes and pathways utilized by ovarian cells to activate and execute apoptosis.^{7, 11} Many of these investigations were carried out in my own lab through extremely productive collaborations with several of the eminent scientists, including Stan, who were leading the charge to quickly assemble a general molecular blueprint of how cell death is regulated in mammals. Importantly, as this work unfolded, it became apparent to us that apoptosis and its gene repertoire were not just involved in the natural or age-related depletion of female germ cells but also contributed in a highly significant way to various models of premature ovarian failure resulting from exposure of females to pathological insults (e.g., chemotherapy, radiotherapy, environmental toxicants).⁷ New possibilities therefore emerged, rooted in the concept of apoptosis-based therapies targeted at the germline, to combat infertility in female cancer patients and, perhaps, even delay the onset of menopause. Indeed, one of these lines of study has progressed through a decade of proof-of-concept testing in mice to reach preclinical evaluation in non-human primates as a critical next step towards possible human application.¹²

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