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the Asian mainland as far east as Java and Bali, but water gaps of 6, 19, and 3 km, re- spectively, 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 mon- keys and buffalo and squirrels also reached Celebes, all surely without making rafts; H. erectus presumably could have as well.
Why haven’t remains of erectus-like hu- mans 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; per- haps 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 re- mains 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-sapiens humans, but also for stegodonts, monkeys, buffalo, and squirrels, none of which are found in Australia and New Guinea.
The discoverers of the Flores micropyg- mies conclude that they survived on Flores until at least 18,000 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. sapi- ens reached Australia and New Guinea through Indonesia by 46,000 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. sapi- ens on all other islands and continents in the world was accompanied by similar waves of extinction/extermination. We also know that humans have exterminated competing hu- mans 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 sapiens and pygmy sapiens in the Congo and Philippines, based on complementary economies, with pygmy hunter-gatherers trading forest products to full-sized sapiens farmers. But full-sized sapiens hunter-gath- erers 18,000 years ago would have been much too similar economically to micropyg- my 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 economical- ly 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 12,000 years ago (1, 2): If stegodonts sur- vived 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 46,000 years ago within a century of H. sapiens’ arrival on Flores. All of these analogies and sug- gestions strike me as implausible: I just can’t conceive of a long temporal overlap of sapi- ens and 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 re- ported coexistence.
At last comes the question that all of us full-sized sapiens wanted to ask but didn’t dare: Did full-sized sapiens have sex with micropygmies? The difference in body size would not have been an insuperable obsta- cle: 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, be- cause chimps are too unlike humans to ap- peal sexually to most of us, and because chimps are much too strong, unpredictable, and dangerous to make sex a safe proposi- tion for any individual humans who might find them sexually attractive. Ditto for H. erectus, even when dwarfed.
References 1. P. Brown et al., Nature 431, 1055 (2004). 2. M. J. Morwood et al., Nature 431, 1087 (2004). 3. G. P. Burness, J. Diamond, T. Flannery, Proc. Natl. Acad.
Sci. U.S.A. 98, 14518 (2001). 4. R. Jones, in Sunda and Sahul, J. Allen, J. Golson, R.
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N ucleic acids are best known as the carriers of genetic information, but they are also a versatile material for
designing nanometer-scale structures, be- cause nucleic acid sequences can be de- signed such that the strands fold into well- defined secondary structures. In 1982, Seeman (1) first proposed using branched DNA building blocks to construct ordered ar- rays. In recent years, DNA has been shown to be an ideal molecule for building microme- ter-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 com- plex 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 ra- tionally designed RNA building blocks as jig- saw puzzle pieces that direct pattern forma- tion. 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 cre- ate 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
M AT E R I A L S S C I E N C E
Nucleic Acid Nanotechnology Hao Yan
The author is at the Biodesign Institute and the Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, USA. E-mail: firstname.lastname@example.org
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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 de- vice 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. Further- more, all polymer reactants exist simultane- ously in one solution. These features make the device appealing for building nanometer- scale 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 bond- forming 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-dimension- al RNA building blocks that assemble into jigsaw puzzle pieces; the pieces then as- semble further into a variety of two-dimen- sional, nanometer-scale structures with in- creasing 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 pre- formed tectosquares as modular building blocks that assemble into addressable pat- terns via sticky-tail connectors. The connec- tors are single-strand overhangs that pro- trude 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 us- ing 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 se- quences, tail lengths, and tail orientations. They combined them to construct 22 tec- tosquares that were subsequently mixed to generate nine different, predefined, finite, and periodic patterns.
RNA tectosquares provide a new tool- box for nucleic acid–based nanotechnolo- gy. How complex can the patterns be? In 1996, Winfree (9) proposed that if self- assembly 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 uni- versal computing is a form of computing that can emulate any other computing method).
Further progress in constructing molec- ular devices and patterned superstructures based on nucleic acids will require meth- ods to reduce errors in self-assembly, to template functional nanoelectronics on nanometer-scale DNA fabrics, to extend two-dimensional self-assembly to three di- mensions, and to scale up self-assembly. Recent progress on error-correcting mech- anisms (11), molecular lithography based on DNA-based nanometer-scale assemblies (12, 13), DNA-templated metallic nanopar- ticle arrays (14), and a replicable, three- dimensional, nanometer-scale DNA octa- hedron (15) promises an exciting future for nucleic acid nanotechnology.
References and Notes 1. N. C. Seeman, J. Theor. Biol. 99, 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.
Neumann, Nature 406, 605 (2000). 5. S. Liao, N. C. Seeman, Science 306, 2072 (2004). 6. A. Chworos et al., Science 306, 2068 (2004). 7. M. W. Kanan et al., Nature 431, 545 (2004). 8. E. Westhof, B. Masquida, L. Jaeger, Fold Des. 1, R78
(1996). 9. E. Winfree, in DNA Based Computers, R. J. Lipton, E. B.
Baum, Eds. (American Mathematical Society, Providence, RI, 1996), pp. 199–221.
10. P. W. K. Rothemund, N. P. Papadakis, E. Winfree, PLoS Biol. 2, e424 (2004).
11. E. Winfree, R. Bekbolatov, in DNA Computing 9, J. Chen, J. Reif, Eds. (Springer, Berlin, 2004), pp. 126–144.
12. Z. X. Deng, C. D. Mao, Angew. Chem. Int. Ed. 43, 4068 (2004).
13. K. Keren et al., Science 297, 72 (2002). 14. J. D. Le et al., Nano Lett., published online 29 October
2004 (10.1021/nl048635+). 15. W. M. Shih, J. D. Quispe, G. F. Joyce, Nature 427, 618
(2004). 16. I thank NSF and the Biodesign Institute at Arizona
State University for financial support.
Ribosome-like DNA device
Subsection 1 Subsection 2
Polymers to be aligned
Positional alignment of polymers Polymer products
Simplified drawing of a ribosome- like 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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