DNA nanotechnology. DNA nanotechnology grows up.

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C R E D IT : A D A P T E D F R O M Y U H E E T A L ., N A T U R E N A N O T E C H N O L O G Y 5 ( N O V E M B E R 2 0 1 0 ) DNA nanotechnology isn’t only about using DNA as a set of tiny Tinkertoys. Researchers in the fi eld have long sought to use DNA’s ability to store and manipulate information to build a DNA computer. But after years of trying—and failing—to outdo conventional computer technology, the fi eld is fi nally advancing by going back to DNA’s biochemical roots. The appeal of a molecular computer is easy to see. A single gram of dried DNA contains roughly as much information as 1 trillion compact discs. And the fact that life exists and evolves shows that this information can be stored, read out, manipulated, and copied. In short, it can be used for computation. In principle, the selective binding and unbinding of complementary DNA strands can even be used to process vast amounts of information in parallel. In 1994, Leonard Adleman, a computer scientist at the University of Southern California in Los Angeles, harnessed that power to solve a so-called Hamiltonian path problem, a version of the well-known “traveling salesman problem” that computer scientists use as a benchmark for tough computations (Science, 11 November 1994, p. 1021). Later, Adleman and other researchers moved on to far more complex problems. The idea of using DNA to perform conventional computations, however, quickly fi zzled out. “We gave up on that back around 1998,” says Erik Winfree, a DNA computation expert at the California Institute of Technology (Caltech) in Pasadena. DNA computers, Winfree notes, are slow, error-prone, and diffi cult to scale up to perform millions of operations. That makes them impractical for tasks that microelectronics does well. Instead, Winfree and others argue, DNA computers should play to their strength: processing information inside organisms or other wet environments where conventional computer chips can’t go. “The real application is making slow, crappy computers that can talk to cells,” enabling them to do things such as diagnose and treat diseases, says William Shih, a biological chemist at Harvard Medical School in Boston. “You don’t need [Intel’s] Core 2 Duo processor to do that.” A striking example of this approach came last year from the laboratory of Niles Pierce, one of Winfree’s colleagues at Caltech. In an article published online 7 September 2010 in the Proceedings of the National Academy of Sciences, Pierce and Caltech colleagues described how they had used pairs of small synthetic molecules of DNA’s short-lived cousin RNA to diagnose and kill tumor cells in vitro. The fi rst RNA strand was designed to recognize and bind to an RNA unique to cancer cells. Latching on to the cellular RNA caused the strand to expose a binding site to which the second RNA could attach itself. That second binding, in turn, unleashed a chemical cascade that made the cancer cell think it had been infected with a virus and triggered the cell to kill itself. Noncancer cells, meanwhile, were spared. Pierce and his colleagues also reported online 31 October in Nature Biotechnology that a related strategy could be used to image RNA expression inside cells. To researchers in the fi eld, such sensor-triggered step-by-step processes represent biological computer programs. Chemists are also getting in on the act, using tiny DNA “walkers” to help them build molecules. DNA walkers are rudimentary DNA robots designed to move step by step down a linear track. The robots’ legs are DNA strands that bind to specifi c complementary DNAs on a predesigned surface. Although there are many types of walkers, most take a step each time researchers add a specifi c DNA snippet, known as a “fuel” strand, to their brew. Each fuel strand acts like a computer command telling the walker what to do next. The fi rst fuel strand binds the site on the track holding the back “leg” of a two-legged walker, causing it to unbind from its DNA partner on the surface, and then bind to another DNA sequence past the front leg. Another snippet is then added to move the second leg forward, and so on. In 2010, three groups took the idea a big step forward by putting DNA walkers to work as construction crews. In the 13 May 2010 issue of Nature, Nadrian “Ned” Seeman, a DNA nanotech expert at New York University, and his colleagues described creating a fl eet of DNA walkers, each with four legs and three DNA arms designed to pick up and move various pieces of molecular cargo. Seeman’s DNA walkers linked their successive loads into a growing molecule, creating perhaps the world’s smallest assembly line. Groups led by Andrew Turberfi eld, a physicist at the University of Oxford in the United Kingdom, and David Liu, a chemist at Harvard University, built related construction robots a short while later. And earlier this year, Turberfi eld and his team reported in Nano Letters that they had programmed their cargo-carrying walkers to move in desired directions down a track with multiple branches that are preprogrammed to display synthesized DNA with binding sites specifi c to DNA stretches on the legs of the walkers. In the future, Turberfield says, researchers might be able to program multiple robots to construct a wide variety of different molecules simultaneously. For now, these and other DNA machines are slow and simple. But they’ve already proved that they can manipulate information in ways that microelectronics may never be able to match. –R.F.S. R3