In fall 2015, ASCB awarded the first-ever ASCB-Gibco Emerging Leader Prizes to three cell biology researchers. ASCB introduced the prizes to honor not-yet-tenured independent investigators with outstanding scientific accomplishments and strong publication track records. The prizes were underwritten by Gibco, a brand of Thermo Fisher Scientific.
ASCB President Peter Walter invited each of the prize winners and each of the seven additional finalists to contribute an essay to the ASCB Newsletter. The writers were encouraged to provide a personal statement that articulates who they are, their science, and how they got into it; to describe their major scientific accomplishments; and to discuss their “dream results” and where they see themselves in the next five years.
This issue of the Newsletter features the essays of finalist Kelly Monk and winner Meng Wang.
Kelly Monk
I was born and raised in Ohio and the product of a magnet school for the arts, but my life changed at 14 when I won an essay contest to attend a marine biology summer camp in the Florida Keys. There I was exposed to and delighted in learning about
Kelly Monk – Washington University in
St. Louis
island ecology, coral reef biology, and marine science. I attended Elmira College, a small liberal arts school in upstate New York, in part because of a travel abroad program that allowed me to once again study marine and island ecology, this time on San Salvador Island. While a love for marine biology still runs deep in me, throughout college and in summer undergraduate research programs, I became very interested in cell biology—specifically, the myriad cell types and cell–cell interactions found in the nervous system.
When thinking of cells in the nervous system, most people first consider neurons. Yet diverse cells called glia can vastly outnumber neurons in some regions of the human brain. As a graduate student in the lab of Nancy Ratner at Cincinnati Children’s Hospital, I began to work on a subset of glia—myelinating glia—and I have happily devoted myself to understanding these cells ever since. The lipid-rich myelin sheath, the “white” in “white matter,” insulates axons in the vertebrate nervous system and comprises ~50% by volume of the adult human brain. Myelin is generated by specialized glial cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), that wrap their membranes around an axonal segment many times to form the multilamellar sheath. Whereas myelin has historically been considered largely in the context of its key role in facilitating fast impulse propagation, this view is rapidly expanding, with myelin and myelinating glia also having diverse and essential functions in nervous system development, maintenance, plasticity, and repair.
At birth, the human brain is scantly myelinated, and robust myelination proceeds well into the fourth decade of life. From this observation a number of questions arise:
- At the organismal level, how does this remarkable expansion of myelinated axon tracts impact neural circuits, learning, and behavior?
- At the cellular level, how are axons selected to be myelinated?
- How is myelination initiated and what controls the spiral wrapping of glial cell cytoplasm around axons?
- What molecular pathways ensure proper axon–glial and glial–glial communication?
- What signals are essential to maintain myelin after it has formed, and what pathways control remyelination in disease and injury?
My lab at Washington University opened its doors in 2011, and we have been using a synergistic combination of zebrafish and mouse models to tackle these questions. Myelin is an evolutionary innovation of the jawed vertebrate lineage; thus, zebrafish represent the simplest model system in which to elucidate the molecular genetic and cellular mechanisms of myelination. Via a forward genetic screen in zebrafish, as a postdoctoral fellow in Will Talbot’s lab at Stanford University I helped to discover that a then-orphan adhesion G protein–coupled receptor (aGPCR) is essential for glial cell development and myelination in zebrafish and mice. This, excitingly, defined a new receptor class that controls myelination and opened many new areas of investigation. aGPCRs are, like glia, rather understudied; they are unique proteins defined structurally by a large extracellular region linked to a canonical seven-pass transmembrane domain via a specialized domain where receptor autoproteolysis can occur.
By leveraging genome-editing capabilities in zebrafish and mouse, we have begun to define the repertoire of aGPCRs required in myelinating glial cell development and myelin repair. We have also contributed to the rapidly growing and dynamic aGPCR field by defining new ligands and activation mechanisms for this enigmatic receptor class. The first five years of setting up a lab and working with the extraordinarily talented students and postdocs brave enough to join a new PI’s lab have been more fulfilling than I could have imagined. I’m delighted to realize that from this point forward, I will able to celebrate not only our continued discoveries in the lab, but also the future discoveries and successes of my trainees who are heading to their postdoctoral positions and setting up their own labs.
Meng Wang
Meng Wang –
Baylor College of Medicine
I received a BS in Biochemistry and Molecular Biology from Peking University in 2001. In 2005, I received a PhD in Genetics from the University of Rochester. During my graduate studies, I worked under the supervision of the fly geneticist Dirk Bohmann and became interested in the molecular genetics of aging. I discovered that JNK signaling functions as a novel longevity-regulatory pathway and unveiled a previously unknown interaction between JNK and insulin signaling in regulating development, stress, and aging. Pursuing my postdoctoral training with Gary Ruvkun at Harvard Medical School and Massachusetts General Hospital, I switched from Drosophila to Caenorhabditis elegans while maintaining my strong interest in aging biology. My postdoctoral work brought to light an unexpected link between lipid metabolism and longevity. In September 2010 I became an assistant professor in the Department of Molecular and Human Genetics at Baylor College of Medicine and was also appointed as an endowed Fyfe Scholar in the Huffington Center on Aging.
My laboratory aims to understand the molecular genetics of lipid metabolism, reproductive senescence, and somatic aging. These intertwined biological processes exert profound influence on human health, and aberrations in them are major risk factors for various chronic and degenerative diseases. My laboratory has been studying the molecular mechanisms governing these key biological processes and their complex interrelationship by combining powerful genetics and genomics of C. elegans together with biochemical, metabolomic, bioengineering, and optical biophysical approaches. This research advances our knowledge of the fundamental mechanisms of somatic and reproductive aging and develops innovative techniques to investigate the molecular basis governing lipid dynamics.
We have uncovered a novel signaling role of lysosomes in regulating longevity, and delineated the first lysosome-to-nucleus retrograde lipid messenger pathway. In a genome-scale analysis, we discovered new genes and pathways that regulate reproductive longevity, revealing the previously uncharacterized humoral effects of mating on female reproductive senescence. We also elucidated a previously unreported neuroendocrine nexus linking olfactory sensation to reproductive aging, laying the groundwork for further investigation of environmental impact on reproductive health. Excitingly, these mechanistic studies also pinpointed beneficial natural compounds, which will be compelling targets for developing new nutraceutical therapies to improve metabolic health and longevity.
Our technological developments aim to tackle a long-standing challenge in cell biology—how to sensitively and specifically trace in vivo dynamics of lipid molecules in cells and organisms. Lipid molecules are intrinsically non-fluorescent, and fluorescence labeling often alters their chemical activities, which makes those molecules invisible to traditional imaging methods. Through collaboration with Sunney Xie at Harvard University and Min Wei at Columbia University, we developed imaging platforms based on stimulated Raman scattering (SRS) microscopy for visualizing lipid molecules in live organisms. We assembled the first SRS-screening platform, leading to the discovery of new lipid regulatory genes. We also developed hyperspectral and isotope-labeling-coupled SRS microscopy systems to visualize different classes of lipid molecules and trace their temporal dynamics in real time. These new technological platforms provide us unique opportunities to investigate previously unknown aspects of lipid dynamics and their regulatory mechanisms.
In the next five years, I will further combine new technology development and in-depth mechanistic studies, with a focus on metabolite-directed cellular communication. Metabolic activity is at the nexus of cellular homeostasis, and metabolomics has identified thousands of intermediates and products as metabolites. In addition to their well-known functions as structural building blocks and energy sources, these natural metabolites can also function as signaling molecules. I wish to discover these signaling metabolites, dissect their regulatory network, and reveal their impacts on metabolic fitness and organism longevity.
