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Xie and team
Those who worked on the paper include Jie Xiao (left), Ji Yu, Sunney Xie, Nir Friedman, and Long Cai. (Photo by Paul Blainey)

Molecule by molecule, new assay shows real-time gene activity

First 'movie' of gene expression in live cells shows proteins being made in small bursts

By Steve Bradt
FAS Communications

Protein production videos:
Video 1 (Quicktime)
Video 2 (Quicktime)

Chemists at Harvard University have developed the first technique providing a real-time, molecule-by-molecule "movie" of protein production in live cells. Their direct observation of fluorescently tagged molecules in single cells - providing striking real-time footage of the birth of individual new protein molecules inside - greatly increases scientists' precision in probing genetic activity.

Using the new assay, described this week in the journal Science, researchers led by Harvard's X. Sunney Xie counted, one by one, protein molecules generated in small bursts within cells as multiple ribosomes bound to single copies of mRNA complete the process by which DNA, an organism's long-term genetic repository, yields its crop of proteins. These random, or stochastic, bursts of protein expression are described in detail in a separate paper Xie and colleagues present this week in Nature.

"Although central to life processes, the expression of many important genes takes place at very low levels, making it difficult or impossible to observe using current technologies," says Xie, professor of chemistry and chemical biology in Harvard's Faculty of Arts and Sciences. "Our experiments provide the most sensitive means to date of observing real-time activity of single molecules inside cells. This new technique could provide us with unprecedented insights into gene expression and many other fundamental biological processes in living cells."

The central dogma of molecular biology holds that DNA is transcribed into mRNA, which is then translated into proteins. But several technical hurdles have hampered study of these key processes. Researchers' current understanding of this two-step pathway is built upon their averaging of genetic and biochemical activity across large populations of cells and molecules, masking the essential randomness of the process at the cellular level. Furthermore, much of our knowledge on the workings of the molecular machinery involved in gene expression comes from experiments done in vitro, rather than in living cells. Finally, the low sensitivity of current techniques for detecting gene expression has restricted analysis to highly expressed genes.

Xie's new assay addresses all three limitations.

"Dr. Xie's experiments are the first to obtain quantitative, real-time information on protein expression in living cells at the single-molecule level," says Jeremy M. Berg, director of the National Institute of General Medical Sciences, which funded the work in part. "His imaging methods open up new possibilities for addressing fundamental questions about the precise events and factors involved in regulating these essential processes. This is exactly the sort of highly innovative research with broad applicability that the National Institutes of Health (NIH) Director's Pioneer Award was created to support."

Xie's Science co-authors are Ji Yu, Jie Xiao, and Xiaojia Ren at Harvard and Kaiqin Lao of Applied Biosystems. His Nature co-authors are Long Cai and Nir Friedman at Harvard. The work was funded by the NIH's Director's Pioneer Award, the U.S. Department of Energy's Office of Science's Genomics: GtL program, Applied Biosystems, and Merck.

Copyright 2007 by the President and Fellows of Harvard College