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Reinventing the cell
Rockefeller physicists create a “cell free” system capable of carrying out biological processes
To physicists, a cell isn’t the ideal place to do science.
Physics is a discipline based on concrete laws and defined order, and the building blocks of life are messy and unpredictable. That puts Albert Libchaber, head of the Laboratory of Experimental Condensed Matter Physics, in a prickly situation. He studies, among other things, gene expression — which requires living cells.
Or, maybe, it doesn’t.
In what may be the initial step towards building a “minimal cell,” Libchaber has designed the first fully functional three gene network in vitro that processes genetic input and manufactures proteins. Based entirely on off-the-shelf biochemical components, this network is the first step toward harnessing the informational process found in biological systems.
“Biological researchers are adept at reverse engineering the cell,” says Libchaber. “As physicists studying biological systems, we are more interested in forward engineering based on the laws of biology.”
Libchaber and his colleagues’ genetic network, published recently in the Proceedings of the National Academy of Sciences, is analogous to a conventional electrical circuit — that of a flashlight, for example. A cell-free extract is used as a battery to carry out transcription and translation. RNA polymerase is the input that drives expression of gene clones into plasmids, the hardware of the system.
Output of the circuit is measured with reporter proteins, the firefly luciferase or a green fluorescent protein. Both are visible as either bioluminescent or fluorescent molecules when viewed under a microscope.
Other scientists have developed single-gene systems, but this is this first time a three-gene “cell free” system has worked. The key to success, Libchaber’s team discovered, is in carefully balancing transcription chemistry against translation chemistry, an insight that paves the way for Libchaber and his two postdoctoral associates, Vincent Noireux and Roy Bar-Ziv, to combine synthetic gene expression with other features of cellular function.
Next steps may include: artificial cell membranes, followed by nanopores, to allow small molecules to move through that membrane, and, ultimately, reproduction capabilities for the tiny structures.
“Biology provides a great model for creating a self-replicating machine,” says Libchaber. “Von Neumann proposed some mechanisms for it; Watson and Crick revealed the basis for it. This type of research is what physicists can do.”
Though cell-free protein synthesis is still nascent, Libchaber’s genetic network demonstrates how proteins could someday be manufactured far more efficiently and precisely than current techniques allow, a prospect that has far-reaching implications for the biotech industry.

December 12, 2003



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