Artificial DNA-based circuits could someday program cellular behavior, authors say
By Melissa Lee Phillips | November 15, 2007
Researchers have made an important leap in designing DNA-based circuits, reports this week's Science. They've created the first system that allows amplification of desired DNA sequences without using enzymes -- a step towards creating artificial biochemical circuits inside cells.
"They've begun to develop a programming language, a software, for DNA," said Andrew Ellington of the University of Texas at Austin. The work is "a significant advance over previous [attempts]," he added.
Scientists have previously used DNA to build synthetic biochemical circuits. But these networks have generally only been designed to perform one task. "These were machines that carried out a particular function or solved a particular problem," Ellington told The Scientist.
In the new work, "we show a method of designing them generally so that it can be applied basically to any sequence you want," said first author David Yu Zhang of the California Institute of Technology in Pasadena.
Zhang and his colleagues created a network of reactions based on the base-pairing of six short, single-stranded DNA pieces. Domains on each DNA strand determine how the circuit components interact with each other.
In each reaction, a DNA catalyst binds to a complementary DNA strand and displaces two other strands. Because this leads to increased disorder overall, the reaction is thermodynamically favorable. Unlike biological catalysis, the reaction requires no enzymes.
Using this system, the authors achieved two types of signal amplification found in natural biological regulatory networks. They created a feedback amplification system, in which a reaction's product catalyzes its own reaction. According to the authors, such an autocatalytic system could eventually become an enzyme-free alternative to the polymerase chain reaction (PCR). They also created a chain of reactions that amplifies a desired final piece of DNA. "We can cascade these catalysts and have a serial amplification, kind of like a signal transduction system," Zhang said.
Although they performed their work in DNA, the system should work equally well with RNA or synthetic nucleic acids, Zhang said. Ultimately, the goal of this type of research is to create independent networks that could operate in parallel to biological cellular networks, Zhang said. Such synthetic circuits could potentially detect aberrations in cellular functioning and respond by initiating "some therapeutic action that would be directed only to that cell," said John SantaLucia of Wayne State University in Detroit and DNA Software, Inc., in Ann Arbor, who wasn't involved in the work.
The authors also showed that their circuits perform well in the presence of animal RNA and cell lysate--an important demonstration if such circuits are to be used inside cells, SantaLucia said.
The system the researchers created is both simpler and more robust than any previous attempts, SantaLucia added. It may not be appropriate for technologies such as DNA-based computers that would require very complex computations, he said, but it would likely work well for "the kind of simple computations that you could do inside of a cell."
Melissa Lee Phillips
Links within this article:
"Engineering entropy-driven reactions and networks catalyzed by DNA," Science, November 16, 2007.
J. Lucentini, "Is this life?" The Scientist, January 1, 2006.
I. Oransky, "Molecular OS gets upgrade," The Scientist, October 11, 2004.
N.C. Seeman, "From genes to machines: DNA nanomechanical devices," Trends in Biochemical Sciences, March 2005.
David Yu Zhang
W. Gloffke, "Quantitative PCR update," The Scientist, April 21, 2003.
S. Karkare, D. Bhatnagar, "Promising nucleic acid analogs and mimics: characteristic features and applications of PNA, LNA, and morpholino," Applied Microbiology and Biotechnology, August 2006.