Finding the secret of immortality has been a persistent dream since the beginning of human civilization. Tales of the Fountain of Youth have appeared in different cultures for thousands of years, with a prominent historic event being the Spanish explorer Juan Ponce de Leon reached Florida in year 1531 on a trip searching for the Fountain of Youth. Another legend says from 219BC and 210 BC the first Chinese emperor sent Fu Xu to find the exlixir of life, who together with his fleet, eventually reached Japan. While human immortality is only a dream, these legends reflect a long noticed observation that the development of an organism is likely unidirectional, such as a human being from infant to adulthood, but not the reverse process. At cellular level, embryonic stem cells (ESCs), as derived from the inner cell mass of an early stage embryo called blastocyst, can differentiate into any of the over 220 cell types found in the adult body, but the reverse dedifferentiation process was once firmly believed as impossible. The Waddington’s epigenetic landscape is an often used metaphor for this irreversible developmental process: a ball slides along a slanted landscape from higher (less-differentiated) to lower (differentiated) regions, and may bifurcate into different valleys corresponding to different cell types. Interestingly, in recent years there are explosive amount of reports on reprogramming terminally differentiated cells into pluripotent stem cells or another differentiated cell types, contradicting this deeply rooted paradigm in developmental biology. Cell type reprogramming has raised great hope in many areas of medical sciences, such as replacing aged or dysfunctioned organs by cultured ones.
Then, how do thousands of molecules species orchestrate temporally and spatially to determine a cell phenotype? How can one regulate and direct cell phenotype? Combined theoretical and experimental systems biology approaches are needed to investigate these complex processes.
My lab currently focuses on Epithelial-to-Mesenchymal Transiton (EMT). EMT is defined as the conversion of epithelial cells to mesenchymal cells, characterized by loss of cell-cell adhesion and increased cell motility. EMT plays important roles in embryonic development, tissue regeneration, wound healing and pathological processes such as fibrosis in lung, liver, and kidney, and cancer metastasis. Thus, in both physiological and pathological contexts quantitative characterization of the EMT process is fundamental for resolving the controversy, and potentially guiding prevention and treatment of cancer metastasis and organ-degenerative diseases. The significance can be seen from the statistic analysis that chronic fibroproliferative diseases contribute to nearly 45% of all deaths in the developed world.
In a theoretical paper, we show that EMT is a sequential two-step program in which an epithelial cell first is converted to partial EMT then to the mesenchymal state, depending on the strength and duration of TGF-β stimulation. Mechanistically the system is governed by coupled reversible and irreversible bistable switches. The SNAIL1/miR-34 double-negative feedback loop is responsible for the reversible switch and regulates the initiation of EMT, whereas the ZEB/miR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-β/miR-200 feedback loop makes the second switch irreversible, modulating the maintenance of EMT. Then our experimental studiesconfirmed all of our model predictions. Currently we are studying the coupled gene expression and epigenetic dynamics of EMT.