158 3 REPRODUCTIONFOCUS REVIEW WOMEN IN REPRODUCTIVE SCIENCE Lessons from bioengineering the ovarian follicle: a personal perspective Teresa K Woodruff Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Correspondence should be addressed to T K Woodruff; Email: [email protected] This paper forms part of a focus section on Women in Reproductive Science. The guest editor for this section was Professor Marilyn Renfree, Ian Potter Chair of Zoology, School of BioSciences, The University of Melbourne, Victoria, Australia Abstract The ovarian follicle and its maturation captivated my imagination and inspired my scientific journey – what we know now about this remarkable structure is captured in this invited review. In the past decade, our knowledge of the ovarian follicle expanded dramatically as cross-disciplinary collaborations brought new perspectives to bear, ultimately leading to the development of extragonadal follicles as model systems with significant clinical implications. Follicle maturation in vitro in an ‘artificial’ ovary became possible by learning what the follicle is fundamentally and autonomously capable of – which turns out to be quite a lot. Progress in understanding and harnessing follicle biology has been aided by engineers and materials scientists who created hardware that enables tissue function for extended periods of time. The EVATAR system supports extracorporeal ovarian function in an engineered environment that mimics the endocrine environment of the reproductive tract. Finally, applying the tools of inorganic chemistry, we discovered that oocytes require zinc to mature over time – a truly new aspect of follicle biology with no antecedent other than the presence of zinc in sperm. Drawing on the tools and ideas from the fields of bioengineering, materials science and chemistry unlocked follicle biology in ways that we could not have known or even predicted. Similarly, how today’s basic science discoveries regarding ovarian follicle maturation are translated to improve the experience of tomorrow’s patients is yet to be determined. Reproduction (2019) 158 F113–F126 Introduction needing to be purified by each lab. The chemically laborious Maxim–Gilbert sequencing method was also Sitting proudly on my desk is a first edition of Regnier giving way to the enzymatically elegant Sanger dideoxy De Graaf’s treatise on the ovarian follicle (de Graaf sequencing method. Within 4 years of publishing the rat 1672), given to me by my great friend Najiba Lalou on inhibin sequence, graduate students like me, would no the occasion of my investiture as the Thomas J Watkins longer be cloning, sequencing, and publishing genetic Chair of Obstetrics and Gynecology at Northwestern data – those tasks would become the purview of The University (Box 1). As strange as it may sound, I have Human Genome Project. loved the ovarian follicle and its cyclical rhythm since A little over a decade passed in which I continued my first introduction to the structure in graduate school. my work on the inhibins and activins, their cyclical My PhD thesis advisor, Dr Kelly Mayo, had cloned a regulation in and release from the ovarian follicle, and gene expressed by the human ovarian follicle, the inhibin their function in the reproductive axis. I collaborated α-subunit (Mayo et al. 1986). My task was to clone the with Dr Tom Thompson to solve the crystal structure inhibin subunits from rats and sequence the associated of activin with its receptor and binding proteins, genes, and then determine their molecular regulation elucidating key functional domains and shedding during the reproductive cycle (Woodruff et al. 1987, light on how the inhibin and activin ligands may have 1988, 1989, 1991, D’Agostino et al. 1989, Woodruff & co-evolved (Thompson et al. 2003, 2005, Cook et al. Mayo 1990, Makanji et al. 2014b). At the time, cloning 2005, Lin et al. 2006, 2011, Lerch et al. 2007a,b, Zhu of genes was reaching a fever pitch, with reagents like et al. 2010). Having the right tools at the right time is restriction enzymes available for purchase rather than a critical part of the advancement of science, and a © 2019 Society for Reproduction and Fertility https://doi.org/10.1530/REP -19-0190 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via https://rep.bioscientifica.com Downloaded from Bioscientifica.com at 09/30/2021 03:49:35PM via free access -19-0190 F114 T K Woodruff Box 1 Teresa K Woodruff PhD is the Dean and Associate Provost for Graduate Education in The Graduate School at Northwestern University. She is also the Thomas J Watkins Professor of Obstetrics & Gynecology, the Vice Chair for Research and the Chief of the Division of Reproductive Science in Medicine in the Department of Obstetrics and Gynecology, Feinberg School of Medicine. She is the Professor of Molecular Biosciences in the Weinberg College of Arts and Sciences and Professor of Biomedical Engineering in the McCormick School of Engineering. She is the Director of the Center for Reproductive Science (CRS), Founder and Director of the Women’s Health Research Institute (WHRI) and Director of the Oncofertility Consortium. She is an internationally recognized expert in ovarian biology and, in 2006, coined the term ‘oncofertility’ to describe the merging of two fields: oncology and fertility. She now heads the Oncofertility Consortium, an interdisciplinary team of biomedical and social scientist experts from across the country. She has been active in education not only at the professional level but also with high school students. In 2011, she was awarded the Presidential Award for Excellence in Science Mentoring in an oval office ceremony by President Obama. Prof Woodruff holds more than 10 U.S. Patents, and was elected to the National Academy of (2017). Her honors include a Guggenheim Fellowship (2017), the Society for Endocrinology Transatlantic Medal (2017), a Leadership Award from the Endocrine Society (2017) and the Mentor of the Year Award from the Society for the Study of Reproduction (2018). She has two honorary degrees, including one from the University of Birmingham, College of Medical Studies, UK (2016) and one from Bates College (2011). She is an elected member of the National Academy of Medicine (2018), a fellow of the American Institute of Medical and Biological Engineering (2017) and the American Association for the Advancement of Science (AAAS; 2005). She is past-president of the Endocrine Society and championed the new NIH policy that mandates the use of females in fundamental research. She currently serves as Editor-in-Chief of Endocrinology. She is civically active and is an elected member of The Economic Club of Chicago, The Chicago Network, a member of the Adler Planetary of Chicago Board of Trustees, and previously served on the school board of the Chicago-based Young Women’s Leadership Charter School. Some important articles Ma Y, Oliveira DFM, Woodruff TK & Uzzi B 2019 Women who win prizes get less money and prestige. Nature 565 287–288. (https://doi. org/10.1038/d41586-019-00091-3) Smith BM, Duncan FE, Ataman L, Smith K, Quinn GP, Chang RJ, Finlayson C, Orwig K, Valli-Pulaski H, Moravek MB et al. 2018 The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond. Future Oncology 14 3059–3072. (https://doi. org/10.2217/fon-2018-0278) Laronda MM, Rutz AL, Xiao S, Whelan KA, Duncan FE, Roth EW, Woodruff TK & Shah RN 2017 A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nature Communications 8 15261. (https://doi.org/10.1038/ncomms15261) Xiao S, Coppeta JR, Rogers HB, Isenberg BC, Zhu J, Olalekan SA, McKinnon KE, Dokic D, Rashedi AS, Haisenleder DJ et al. 2017 A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nature Communications 8 14584. (https://doi.org/10.1038/ ncomms14584) Duncan FE, Que EL, Zhang N, Feinberg EC, O’Halloran TV & Woodruff TK 2016 The zinc spark is an inorganic signature of human egg activation. Scientific Reports 6 24737. (https://doi.org/10.1038/srep24737) Zhang N, Duncan FE, Que EL, O’Halloran TV & Woodruff TK 2016 The fertilization-induced zinc spark is a novel biomarker of mouse embryo quality and early development. Scientific Reports 6 22772. (https://doi.org/10.1038/srep22772) Xiao S, Zhang J, Romero MM, Smith KN, Shea LD & Woodruff TK 2015b In vitro follicle growth supports human oocyte meiotic maturation. Scientific Reports 5 17323. (https://doi.org/10.1038/srep17323) Zhu J, Mishra RK, Schiltz GE, Makanji Y, Scheidt KA, Mazar AP & Woodruff TK 2015 Virtual High-Throughput Screening To Identify Novel Activin Antagonists. Journal of Medicinal Chemistry 58 5637–5648. (https://doi.org/10.1021/acs.jmedchem.5b00753) Kim AM, Vogt S, O’Halloran TV & Woodruff TK 2010 Zinc availability regulates exit from meiosis in maturing mammalian oocytes. Nature Chemical Biology 6 674–681. (https://doi.org/10.1038/nchembio.419) Woodruff TK, D’Agostino J, Schwartz NB & Mayo KE 1988 Dynamic changes in inhibin messenger RNAs in rat ovarian follicles during the reproductive cycle. Science 239 1296–1299. (https://doi.org/10.1126/science.3125611) willingness to cross-disciplinary lines and be an early Ovarian follicle maturation is autonomous to adopter or even an inventor is a winning combination. the follicle Here I provide a bit of background on some of the essential tools that my lab has utilized or invented to The ovary can be seen as an artful box that holds learn more about the ovarian follicle and the ways in individual organs called follicles. Each follicle contains which follicles develop over reproductive time. These a single germ cell – the oocyte – and is responsible tools have been prismatic – they have allowed us to for production of the hormones necessary for oocyte peer through them as the light shines in, revealing maturation and for endocrine feedback to the higher multiple facets of follicle biology that feather out in a brain centers within the reproductive axis.