Promoting Diversity via Single-cell Metabolomics and Proteomics: The Missing Link to Understanding Vertebrate Embryonic Patterning

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Abstract The goal of this project is to enhance the diversity of the biomedical research workforce by training a PhD Graduate Student from underrepresented backgrounds to enable their original research and career development at the frontiers of chemistry and biology. The student will learn advanced bioanalytical chemistry and vertebrate embryology while elucidating the mechanism of action underlying cell fate changes by small molecules called metabolites, which the Nemes Research Laboratory has recently discovered. Understanding embryogenesis requires knowledge of all the molecules produced as the zygote differentiates into the three primary germ layers of the embryo. Four decades of innovative embryological manipulations, testing of gene functions one gene at a time, and recently, Next-Generation Sequencing have identified multiple transcripts and abundant proteins that are essential to the patterning of the vertebrate embryo. However, very little is known about the contribution of small molecules called metabolites to the formation of the germ layers and the long-term development and functioning of the embryo. The proposed training–research program fills this knowledge gap in technology and biology by empowering the PhD Graduate Student to conduct original research at the chemistry-biology interface. The student will develop skills in bioanalytical chemistry, specifically quantitative metabolomics by capillary electrophoresis and ultrasensitive electrospray ionization mass spectrometry to enable the characterization of the metabolomic states of cells and tissues. Further, the student will also develop the required biomedical–biological skills to study the developmental and cognitive implications of cell fate decisions, including classical embryological manipulations, cell fate tracking, Xenopus laevis biology, and behavioral assays. The outcomes of this interdisciplinary approach will help illuminate the role of the metabolome for the establishment of these important precursor cells and tissues. Because these molecular processes are highly conserved across vertebrates, the data collected from Xenopus are likely to have high relevance to human structural birth defects. The new biochemical information that will be obtained in individual embryonic cells and their progeny (cell lineage) at several critical developmental time points will also advance other research fields that involve cell differentiation (e.g., of stem cells) and the developmental origins of adult disease. This project will provide immersive cross-disciplinary training–research experience to enable the student to pursue an independent career while diversifying the biomedical research workforce. Nemes-Abstract-1|1