CAREER: Principles and mechanisms of robust embryonic development

Embryos are masterful bioengineers, with the ability to build every organ of the body from a single fertilized egg. This process demands astonishing coordination— millions of cells taking on specialized functions in precisely the right locations— yet embryos build healthy organisms with near perfect regularity. This project aims to understand the origins of this reliability: how do embryos prevent, recognize and correct mistakes before they cause birth defects? The work will be broken up into three interconnected parts. First, the investigators will build and experimentally test a new mathematical theory to explain how embryos communicate error-free instructions to their cells. Second, the investigators will develop and deploy a new microscope technology to observe developmental errors with unprecedented depth and accuracy. Finally, the investigators will engage Pittsburgh-area high school students in experiments to determine how embryos compensate for unexpected changes in external conditions. Over the long run, this work aims to discover new principles that enable bioengineers to build replacement tissues with the reliability and precision of an embryo. Additionally, it aims to inspire the next generation of biologists by providing cutting-edge research experience to high school students. Embryos must communicate precise instructions to their cells. Clear communication is no easy feat, however. An unpredictable environment, random mutations and even noisy intracellular chemistry all threaten to derail orderly development. The principles that enable embryos to function reliably—to be ‘robust’— in the face of such unexpected perturbations remain poorly understood. This study will investigate the origins of robustness in the context of embryo patterning by the Nodal signaling pathway. In previous work, the investigators demonstrated that the zebrafish Nodal patterning system uses signaling feedback to correct perturbations. This project aims to uncover the quantitative principles underlying this correction and determine how variability in cell fate specification is resolved after patterning. In Objective 1, a new, control-theoretic model that explains how signaling feedback implements robust patterning will be formulated and tested. In Objective 2, the investigators develop and apply a new high-throughput imaging approach to measure developmental variability throughout embryogenesis. This work will enhance societal well-being and economic competitiveness by inspiring the next generation of tissue engineering strategies. Further, the high-throughput imaging approach developed in Objective 2 will accelerate the impact of AI on developmental biology and tissue engineering by making it possible to image embryos and organoids at the massive scale required to train cutting-edge deep learning models. Finally, the project will contribute to a globally competitive STEM workforce by inspiring pre-college students with engaging research experiences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2541338 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT,01003031DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Nathan Lord | Institution: University of Pittsburgh, PITTSBURGH, PA | Award Amount: $1,253,324 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2541338 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2541338.html