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Profiles of Pioneers: Class of 2004–2009
Xiaoliang (Sunney) Xie, Ph.D.
Harvard University
Cambridge, MA
 “The Pioneer Award has given me the precious opportunity to pursue [my] most daring ideas, and it has been a special experience for my students. Doing high-risk, high-stakes research is not easy the first time, but if they can succeed once, they will do it again.”
As we learn more about biological systems and their molecular networks, it is important to be able to watch cellular events happen in real time. Can we monitor gene expression—the transcription of DNA to messenger RNA followed by translation to protein—at the single-molecule level in a living cell? Can these studies tell us how cells with identical genes can have such different functions?
The Idea
Dr. Sunney Xie’s Pioneer Award idea was one with far-reaching potential: He wanted to be able to visualize how gene expression and its control takes place in a living cell, one molecule at a time.
To do this, Xie set out to develop new techniques to probe single molecules in living bacterial cells with millisecond time resolution and nanometer spatial precision.
The Results
Xie has recorded single protein molecules being born and has precisely measured how DNA and proteins interact, as well as how gene activity is controlled.
Beginning in 2006, Xie announced the results of a series of breakthrough experiments, starting with the first movie of protein production in a single, living bacterial cell. In 2007, Xie directly monitored the attachment and release of a single transcription factor—a protein that controls gene expression—on DNA. Then, in 2008, Xie discovered that the detachment of a transcription factor from DNA is solely responsible for a cell’s decision to switch from one type to another.
Xie says that it has been very rewarding to apply his single-molecule method to address the fundamental scientific question of how enzymes work as “individuals,” on a single-molecule basis. He has observed that a single enzyme does not have an unchanging reaction rate constant, which contradicts the conventional wisdom based on the classic Michaelis-Menten equation in enzymology. Nevertheless, this fundamental biochemical equation holds true at the level of individual molecules.
In a completely different area, Xie has developed a label-free and chemically selective imaging technique, allowing him to see biological molecules in their natural state. Based on a method called stimulated Raman scattering, the technique detects molecules based on the telltale vibrations of their chemical bonds. For that reason, Xie’s method frees the user from having to label molecules by attaching tags such as gold particles, antibodies or fluorescent proteins. Xie has applied his imaging approach in a variety of ways, such as studying lipid metabolism, mapping distribution of small-molecule drugs and imaging tumors.
Selected Publications
Yu J, Xiao J, Ren X, Lao K, et al. Probing gene expression in live cells, one protein molecule at a time. Science 2006;311:1600-3.
Cai L, Friedman N, Xie XS. Stochastic protein expression in individual cells at the single molecule level. Nature 2006;440:358-62.
English BP, Min W, van Oijen AM, Lee KT, et al. Ever-fluctuating single enzyme molecules: Michaelis-Menten equation revisited. Nat Chem Biol 2006;2:87-94.
Elf J, Li GW, Xie XS. Probing transcription factor dynamics at the single-molecule level in a living cell. Science 2007;316:1191-4.
Choi PJ, Cai L, Frieda K, Xie XS. A stochastic single-molecule event triggers phenotype switching of a bacterial cell. Science 2008;322:442-6.
Freudiger CW, Min W, Saar BG, Lu S, et al. Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy. Science 2008;322:1857-61.
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