There are major inflection points in biomedical discovery that create new fields, new ideas, and new opportunities to impact human health. To recognize scientists at the pinnacle of their fields who have contributed to these inflection points, the Vanderbilt School of Medicine Basic Sciences is launching the Apex Lecture Series. This school-wide seminar series, on occasion partnered with department and/or center seminar series, will bring to campus scientists who are influencing the trajectory of their fields to engage with our scientific community.

Volker Dötsch, Institute of Biophysical Chemistry, Goethe University
Professor of Biochemistry

“Mechanism of Genetic Quality Control in Germ Cells”
Monday, May 22, 2023 (4:00 pm, 1220 MRB III)
Co-sponsored by the Vanderbilt Center for Structural Biology  Add-to-Calendar!

Dr. Dötsch’s research is focused on the understanding of biological structure, function, and interaction at the molecular level. He is known for his highly creative use of biochemical and biophysical techniques to address challenging problems in biomedical research. He is a world-renowned expert in the application of NMR spectroscopy to biological systems and in the production of membrane proteins. Current interests span the range from discerning the roles of cancer tumor suppressor proteins to elucidating mechanisms of protein autophagy.

Abstract: The survival rate of cancer patients is steadily increasing due to better and more efficient therapies. These advances in cancer therapy, however, create a new and increasing problem since treatment with chemotherapeutic drugs and radiation increases the risk of premature ovarian insufficiency (POI) for female cancer patients. While assisted reproductive technologies can address the problem of infertility, these measures cannot restore the hormonal functions pivotal for women’s health. Although recent advances in whole organ replacement could eventually offer an option to restore long-term hormone function and fertility in the future, a more detailed understanding of the molecular mechanisms of therapy-induced POI could identify targets for pharmacological prevention of POI during gonadotoxic therapies. Loss of the primordial follicle reserve is the most important cause of POI. TAp63a, a member of the p53 family, is the central transcription factor that upregulates the apoptotic program in oocytes. In resting primary oocytes it adopts an inactive state by forming a closed, only dimeric conformation. Detection of DNA damage activates the stress kinases CHk1 and CHk2 which leads to the phosphorylation of TAp63a, which itself does not influence the conformation of TAp63a. Instead, it recruits another kinase, CK1, which adds four more phosphate groups C-terminally to the CHk2 site. Electrostatic repulsion between the phosphate groups and a stretch of aspartic acids results in the destabilization of the closed dimeric state and the formation of the open and active tetramer. Measuring the phosphorylation kinetics has further shown that the individual CK1 phosphorylation events follow different kinetic regimes which is part of a kinetically encoded safety mechanism that triggers oocytes death only if a certain DNA damage level threshold is reached. This sophisticated system of monitoring the genetic integrity is evolutionary highly conserved but absent in male germ cells.

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Jason Spence, University of Michigan Medical School
H. Marvin Pollard Professor
Professor of Cell and Developmental Biology, Internal Medicine, Biomedical Engineering

“Interrogating Stem Cell Niches During Human Development”
Monday, May 8, 2023, 12:15 p.m. to 1:15 p.m. CDT, 1220 MRBIII
Co-sponsored by the Department of Cell and Developmental Biology
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Abstract: The Spence laboratory uses pluripotent stem cells as building blocks to create multilineage human organs in vitro. These in vitro organ-like structures – called organoids – have transformative potential, from being used as a model system for human development to being used in translational applications in regenerative medicine, cell replacement therapy, and precision medicine. Our vision of turning stem cells into complex tissues is rooted in asking fundamental questions about being human: How do we develop? What goes wrong during disease? How do we heal? In the past, however, interrogating human development has been limited by small and precious tissue samples. Advances in single-cell transcriptomic and spatial imaging technologies, combined with human stem cell and organoid systems, have recently flipped this paradigm, opening the door to previously unimaginable insights. Our recent efforts have used these experimental approaches to study human organ development across time. By interrogating human organ development, organ-specific stem cells, and stem cell niches, we build hypotheses that can be tested in organoid models and that can lead to the development of new tools to interrogate human biology. From this work, we have generated rich atlases of human organ development, leveraged single-cell data to investigate cellular heterogeneity and identified new cell types, and identified transcriptional and signaling mechanisms that control organ-specific stem cells in vivo. Our current research is aimed at understanding the function of novel cell types, using human stem cell niche factors to develop life-like organoid models from pluripotent stem cells, and interrogating human disease to inform new strategies for tissue repair and regeneration.

Lab website   Twitter: @TheSpenceLab