Nucleic Acid Nanotechnology

Nucleic Acid Nanotechnology

17 DECEMBER 2004VOL 306SCIENCEwww.sciencemag.org2048 the Asian mainland as far east as Java and Bali, but water gaps of 6, 19, and 3 km, respectively, separated Bali from Penida, Penida from Lombok and Sumbawa (joined in the Pleistocene), and Lombok and Sumbawa from Flores and Lomblen (also joined in the Pleistocene) (6). Across each of those water gaps, the island on the far side would have been visible to someone standing on the island on the near side. Hence the micropygmies’ancestors could have colonized the island by sailing toward it in a watercraft (perhaps a rudimentary raft, or a mere floating log), or they could have landed on the island accidentally when their watercraft was swept to sea by ocean currents. Perhaps they even swam to the island. Stegodont elephants reached Flores and Timor and Celebes, and monkeys and buffalo and squirrels also reached Celebes, all surely without making rafts; H. erectuspresumably could have as well.

Why haven’t remains of erectus-like humans been found in Australia and New Guinea, at the eastern end of the Indonesian island chain? Possibly, for the same reason they weren’t found on Flores until 2004; perhaps these humans did reach Australia and New Guinea, but archaeologists just haven’t looked hard enough for their remains. I doubt this answer; hundreds of Pleistocene human sites are now known in Australia, with no remains of humans other than those of sapiens. Instead, the answer probably has to do with geography: A modern map plus bathymetric charts show that, even at Pleistocene times of low sea level, a water gap of at least 87 km separated the easternmost Indonesian islands from either Australia or New Guinea, which would not have been visible across that wide gap (6). Such gaps were too wide not only for pre-sapienshumans, but also for stegodonts, monkeys, buffalo, and squirrels, none of which are found in Australia and New Guinea.

The discoverers of the Flores micropygmies conclude that they survived on Flores until at least 18,0 years ago (1, 2). To me, that is the most astonishing finding, even more astonishing than the micropygmies’ existence. We know that full-sized H. sapiensreached Australia and New Guinea through Indonesia by 46,0 years ago, that most of the large mammals of Australia then promptly went extinct (probably in part exterminated by H. sapiens), and that the first arrival of behaviorally modern H. sapienson all other islands and continents in the world was accompanied by similar waves of extinction/extermination. We also know that humans have exterminated competing humans even more assiduously than they have exterminated large nonhuman mammals. How could the micropygmies have survived the onslaught of H. sapiens?

One could perhaps seek a parallel in the peaceful modern coexistence of full-sized sapiensand pygmy sapiensin the Congo and Philippines, based on complementary economies, with pygmy hunter-gatherers trading forest products to full-sized sapiens farmers. But full-sized sapienshunter-gatherers 18,0 years ago would have been much too similar economically to micropygmy hunter-gatherers to permit coexistence based on complementary economies and trade. One could also invoke the continued coexistence of chimpanzees and humans in Africa, based on chimps being economically too different from us to compete (very doubtful for micropygmies), and on chimps being too dangerous to be worth hunting (probably true for micropygmies). Then, one could point to the reported survival of the pygmy stegodont elephants on Flores until 12,0 years ago (1, 2): If stegodonts survived so long in the presence of H. sapiens, why not micropygmies as well? Finally, one might suggest that all of the recent dates for stegodonts and micropygmies on Flores are in error [despite the evidence presented in (1) and (2)], and that both stegodonts and micropygmies became extinct 46,0 years ago within a century of H. sapiens’arrival on Flores. All of these analogies and suggestions strike me as implausible: I just can’t conceive of a long temporal overlap of sapiensand erectus, and I am reluctant to believe that all of the dates in (1) and (2) are wrong. Hence I don’t know what to make of the reported coexistence.

At last comes the question that all of us full-sized sapienswanted to ask but didn’t dare: Did full-sized sapienshave sex with micropygmies? The difference in body size would not have been an insuperable obstacle: Some individual modern humans have sex with children or with domestic animals no larger than the micropygmies. I suspect that the answer is the same as the answer to the question of whether we modern humans have sex with chimpanzees. We don’t, because chimps are too unlike humans to appeal sexually to most of us, and because chimps are much too strong, unpredictable, and dangerous to make sex a safe proposition for any individual humans who might find them sexually attractive. Ditto for H. erectus, even when dwarfed.

Sci. U.S.A.98,14518 (2001). 4.R.Jones,in Sunda and Sahul,J.Allen,J.Golson,R.

Jones, Eds. (Academic Pr ess, London, 1977), p. 317–386. 5.R.Sim,in Archaeology in the North,M.Sullivan,S.

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10.1126/science.1107565 ucleic acids are best known as the carriers of genetic information, but they are also a versatile material for designing nanometer-scale structures, because nucleic acid sequences can be designed such that the strands fold into welldefined secondary structures. In 1982, Seeman (1) first proposed using branched DNA building blocks to construct ordered arrays. In recent years, DNA has been shown to be an ideal molecule for building micrometer-scale arrays (2,3) with nanometer-scale features. DNA can also be used to make nanometer-scale materials with moving parts, such as nanotweezers (4).

Today, two major challenges face nucleic acid–based nanotechnology: to produce complex superstructures from simple molecular building blocks, and to perform controlled mechanical movements in molecular devices. Two reports in this issue describe steps to meet these challenges. On page 2072, Liao and Seeman (5) present a DNA device that can program the synthesis of linear polymers through positional alignment of reactants. And on page 2068, Chworos et al.(6) use rationally designed RNA building blocks as jigsaw puzzle pieces that direct pattern formation. The two studies demonstrate that it will be feasible to build functional materials and devices from “designer” nucleic acids.

Nanotechnology researchers have sought to mimic nature’s biological motors to create nanometer-scale machines that can function in an engineered environment. Liao and Seeman take an important step in this direction with a device that mimics the translational capabilities of the ribosome. The device consists of two subsections, each with two structural states. Different pairs of DNA “set strands” can be added or removed to bring the device into any one of four states. Each state allows the positional

Nucleic Acid Nanotechnology Hao Yan

The author is at the Biodesign Institute and the Department of Chemistry and Biochemistry,Arizona State Univ ersity, Tempe, AZ 85287, USA. E-mail:

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w.sciencemag.orgSCIENCEVOL 30617 DECEMBER 20042049 alignment of a specific pair of DNA motifs that are selected from a pool. The pairs bear polymer components that can then be fused in a specific order (see the first figure).

As proof of principle, Liao and Seeman use DNA as the polymer that is aligned, and enzymatic ligation to fuse the polymers. Positional synthesis with the prototype device thus results in four different DNA strands, each containing a defined sequence.

In this ribosome-like DNA device, there is no complementary relationship between the signal sequence and the products. Furthermore, all polymer reactants exist simultaneously in one solution. These features make the device appealing for building nanometerscale machines that control massively parallel chemical synthesis. Liu and co-workers (7) have shown that DNA-templated organic synthesis can be used to discover new bondforming chemical reactions.

Future practical applications of nucleic acid–based nanotechnology will depend on our ability to design and self-assemble complex patterns efficiently. Chworos et al.describe exciting progress toward this goal. They have designed three-dimensional RNA building blocks that assemble into jigsaw puzzle pieces; the pieces then assemble further into a variety of two-dimensional, nanometer-scale structures with increasing complexity and addressability.

The jigsaw pieces (RNA tectosquares) each consist of four RNA building blocks (tectoRNA) (see the second figure) (8). Each tectoRNA contains two hairpin loops with a 90°angle between them; four tectoRNAs containing matching hairpin loop sequences can form a RNA tectosquare through noncovalent interactions between their loops. The authors use a pool of preformed tectosquares as modular building blocks that assemble into addressable patterns via sticky-tail connectors. The connectors are single-strand overhangs that protrude from one stem in each building block; by changing the sequence, the orientation of the tail can be varied without changing the positioning of the stem-loop arms (see the second figure). Furthermore, tectosquares of different sizes can be constructed by using hairpin stems of different lengths, thus providing additional degrees of freedom for designing the modular building blocks.

Chworos et al.have synthesized 49 tectoRNAs with different sizes, tail sequences, tail lengths, and tail orientations. They combined them to construct 2 tectosquares that were subsequently mixed to generate nine different, predefined, finite, and periodic patterns.

RNA tectosquares provide a new toolbox for nucleic acid–based nanotechnology. How complex can the patterns be? In 1996, Winfree (9) proposed that if selfassembly proceeds by cooperative binding at multiple weakly binding domains, it should be possible to encode any desired algorithmic rules in a set of “molecular tiles” (such as the RNA tectosquares) that will self-assemble into a potentially quite complex pattern. Indeed, Rothemund et al.

(10) have recently used algorithmic DNA self-assembly to construct a fractal pattern referred to as a Sierpinski triangle; this work demonstrates that engineered DNA self-assembly can be treated as a Turing universal biomolecular system (Turing universal computing is a form of computing that can emulate any other computing method).

Further progress in constructing molecular devices and patterned superstructures based on nucleic acids will require methods to reduce errors in self-assembly, to template functional nanoelectronics on nanometer-scale DNA fabrics, to extend two-dimensional self-assembly to three dimensions, and to scale up self-assembly. Recent progress on error-correcting mechanisms (1), molecular lithography based on DNA-based nanometer-scale assemblies (12, 13), DNA-templated metallic nanoparticle arrays (14), and a replicable, threedimensional, nanometer-scale DNA octahedron (15) promises an exciting future for nucleic acid nanotechnology.

References and Notes 1.N.C.Seeman,J. Theor. Biol.9,237 (1982). 2. E. Winfree, F. Liu, L. A. Wenzler, N. C. Seeman, Nature 394,539 (1998). 3. H.Yan, S. H. Park, G. Finkelstein, J. H. Reif,T. H. LaBean,

Science 301, 1882 (2003). 4. B.Yurke,A. J.Turberfield,A. P. Mills Jr., F. C. Simmel, J. E.

Baum, Eds. (American Mathematical Society , Providence, RI, 1996), p. 199–221. 10. P. W. K. Rothemund, N. P. Papadakis, E. Winfree, PLoS

Biol.2,e424 (2004). 1.E.Winfree,R.Bekbolatov,in DNA Computing 9,J.


Ribosome-like DNA device

Subsection 1Subsection 2

Polymers to be aligned

Set strands

Positional alignment of polymersPolymer products

Simplified drawing of a ribosomelike DNA device that can control positional polymer assembly (5).

TectoRNA building blocks Tectosquares

Programmable jigsaw puzzles

Building programmable patterns with RNA “tectosquares”(6).

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