DNA Nanotechnology - History

History

The conceptual foundation for DNA nanotechnology was first laid out by Nadrian Seeman in the early 1980s. Seeman's original motivation was to create a three-dimensional DNA lattice for orienting other large molecules, which would simplify their crystallographic study by eliminating the difficult process of obtaining pure crystals. This idea had reportedly come to him in late 1980, after realizing the similarity between the woodcut Depth by M. C. Escher and an array of DNA six-arm junctions. A number of natural branched DNA structures were known at the time, including the DNA replication fork and the mobile Holliday junction, but Seeman's insight was that immobile nucleic acid junctions could be created by properly designing the strand sequences to remove symmetry in the assembled molecule, and that these immobile junctions could in principle be combined into rigid crystalline lattices. The first theoretical paper proposing this scheme was published in 1982, and the first experimental demonstration of an immobile DNA junction was published the following year.

In 1991, Seeman's laboratory published a report on the synthesis of a cube made of DNA, the first synthetic three-dimensional nucleic acid nanostructure, for which he received the 1995 Feynman Prize in Nanotechnology. This was followed by a DNA truncated octahedron. However, it soon became clear that these structures, polygonal shapes with flexible junctions as their vertices, were not rigid enough to form extended three-dimensional lattices. Seeman developed the more rigid double-crossover (DX) motif, and in 1998, in collaboration with Erik Winfree, published the creation of two-dimensional lattices of DX tiles. These tile-based structures had the advantage that they provided the capability to implement DNA computing, which was demonstrated by Winfree and Paul Rothemund in their 2004 paper on the algorithmic self-assembly of a Sierpinski gasket structure, and for which they shared the 2006 Feynman Prize in Nanotechnology. Winfree's key insight was that the DX tiles could be used as Wang tiles, meaning that their assembly was capable of performing computation. The synthesis of a three-dimensional lattice was finally published by Seeman in 2009, nearly thirty years after he had set out to achieve it.

New capabilities continued to be discovered for designed DNA structures throughout the 2000s. The first DNA nanomachine—a motif that changes its structure in response to an input—was demonstrated in 1999 by Seeman. An improved system, which was the first nucleic acid device to make use of toehold-mediated strand displacement, was demonstrated by Bernard Yurke the following year. The next advance was to translate this into mechanical motion, and in 2004 and 2005, a number of DNA walker systems were demonstrated by the groups of Seeman, Niles Pierce, Andrew Turberfield, and Chengde Mao. The idea of using DNA arrays to template the assembly of other molecules such as nanoparticles and proteins, first suggested by Bruche Robinson and Seeman in 1987, was demonstrated in 2006 and 2007 by the groups of Hao Yan, Peter Dervan, and Thomas LaBean.

In 2006, Rothemund first demonstrated the DNA origami technique for easily and robustly creating folded DNA structures of arbitrary shape. Rothemund had conceived of this method as being conceptually intermediate between Seeman's DX lattices, which used many short strands, and William Shih's DNA octahedron, which consisted mostly of one very long strand. Rothemund's DNA origami contains a long strand whose folding is assisted by a number of short strands. This method allowed the creation of much larger structures than were previously possible, and which are less technically demanding to design and synthesize. DNA origami was the cover story of Nature on March 15, 2006. Rothemund's research demonstrating two-dimensional DNA origami structures was followed by the demonstration of solid three-dimensional DNA origami by Douglas et al. in 2009, while the labs of Jørgen Kjems and Yan demonstrated hollow three-dimensional structures made out of two-dimensional faces.

DNA nanotechnology was initially met with some skepticism due to the unusual non-biological use of nucleic acids as materials for building structures and doing computation, and the preponderance of proof of principle experiments that extended the capabilities of the field but were far from actual applications. Seeman's 1991 paper on the synthesis of the DNA cube was rejected by the journal Science after one reviewer praised its originality while another criticized it for its lack of biological relevance. By the early 2010s, however, the field was considered to have increased its capabilities to the point that applications for basic science research were beginning to be realized, and practical applications in medicine and other fields were beginning to be considered feasible. The field had grown from very few active laboratories in 2001 to at least 60 in 2010, which increased the talent pool and thus the number of scientific advances in the field during that decade.