Viruses and bacteria act as factories for nanostructures.
Molecular nanostructures — the basic architectural elements of nanotechnology — have been replicated in bacterial cells.
The research proves that nature's cellular machinery can be commandeered to mass-produce complex structures and devices for molecular-scale engineering.
Together with their colleagues, Nadrian Seeman of New York University and Hao Yan of Arizona State University in Tempe speculate that their method might lead to the merging of nanotechnology and Darwinian natural selection, in which such molecular devices could be created and improved by some artificial evolutionary pressure.
The technique, reported in the Proceedings of the National Academy of Sciences1, relies on the fact that the nanostructures in question are made from DNA, the genetic material of living cells.
"This is very interesting", says Chengde Mao, a DNA nanotechnologist at Purdue University in West Lafayette, Indiana. "We're always concerned about the cost of making these structures. But with a method like this, it should be possible to scale up to make large quantities."
In recent years, DNA has emerged as an ideal construction material for nanotechnology because it can be designed and 'programmed' to assemble itself into complicated structures, such as geometric cages and ordered networks2.
It has also been used to make 'machines' with parts that move under external control. These devices and structures rely on DNA's capacity to fold and link into precise shapes by following the rules of base-pairing, which controls the twinning of DNA strands in the double helix of this genetic material.
The pairing principles mean that the architecture of a DNA nanostructure can be predefined by the sequence of its four molecular building blocks, called nucleotides, along a single strand. These components then pair up with complementary strands in a predictable way.
The approach has been used to create DNA 'tiles' that will assemble in a manner designed to carry out computational procedures — a kind of mechanical nanocomputer — and even to create maps of the world that measure just a few nanometres across3.
But making these DNA nanostructures is generally slow and cumbersome. Researchers have figured that, because all cells contain the molecular machinery for replicating genomic DNA with precisely copied sequences, they might be persuaded to make artificial DNA structures instead.
This would, in effect, be a kind of cloning of genetic material — a technique that is already well established in biotechnology. But making it work for artificial, arbitrary DNA sequences that have nothing to do with ordinary genetics is tricky.
Gerald Joyce and colleagues at the Scripps Research Institute in La Jolla, California, have previously managed to clone a DNA strand that will assemble into an octahedral cage, by inserting it into bacteria4. But this nanostructure required five other short strands of DNA to fix it into shape, which couldn't be cloned at the same time.
Seeman, Yan and their co-workers have also developed methods of DNA replication that can be operated in a test tube, using the natural enzyme machinery extracted from cells5. But they suspected that the process would work much more efficiently in living cells, which can replicate exponentially.
To achieve that, they constructed DNA strands that would fold up into two complex nanostructures — a crucifix shape and a complicated double-stranded interweaving structure called a PX molecule — and pasted them into circular double strands of DNA called phagemids. They then inserted these into cells of the gut bacterium Escherichia coli.
In effect, the phagemid acts rather like a viral genome infecting the bacteria. This infection can be propagated to other cells growing in a culture medium with the assistance of a bacterial virus, or phage, called M13KO7. So as the bacteria grow, they end up full of replicated copies of the phagemid, including the segment of DNA that makes the nanostructures.
The researchers then split open the cells and used enzymes to clip the raw DNA out of the phagemid, whereupon it folded up into the designed nanostructures.
Only a tiny amount of initial DNA is needed to start the process, which can be 'amplified' almost indefinitely. And the bacterial cells can be stored as miniature factories ready to churn out the material when required.
Although it may be possible to use Darwinian selection to modify and fine-tune the DNA nanostructures, the researchers would need to find a way of giving a reproductive advantage to those cells that made 'better' nanostructures. Mao suggests that they could design nanostructures with catalytic properties that promote the growth or replication of the host cells.
"So far we haven't talked much about the functions of these DNA structures", says Mao. "But if you can clone them, then it becomes possible to use evolution to address that."
Lin, C . et al. Proc. Natl Acad. Sci. advance online publication (doi:10.1073/pnas.0805416105).
Seeman, N. C. Nature 421, 427–431 (2003).
Rothemund, P. W. K. Nature 440, 297–302 (2006).
Shih, W. M., Quispe, J. D. and Joyce, G. F. Nature 427, 618–621 (2004).
Lin, C. et al. J. Am. Chem. Soc. 129, 14475–14481 (2007).
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Ball, P. Nanotech comes alive. Nature (2008). https://doi.org/10.1038/news.2008.1157