New Scientist vol 177 issue 2386 - 15 March 2003, page 50

The robot within

The tools to create an army of replicating nanobots may lie in your own cells, says Philip Ball

by Philip Ball

They call it "global ecophagy". That's "eating the Earth" to you and me. Rumour has it that this is what replicating nanostructures might do, and according to one estimate, they could gobble up the entire planet in about three hours flat.

So it's a mystery why the announcement by German chemist Gunter von Kiedrowski last December that he is on the brink of making self-replicating objects just nanometres across has passed off so quietly. No one batted an eyelid when von Kiedrowski and his team at the Ruhr University of Bochum reported they can copy the chemical information in complex molecules that are designed to assemble themselves into pre-defined structures.

The idea is that these structures might one day be assembled into tiny robots - nanobots - that could perform incredibly precise tasks. They might prop up failing immune systems, for example, by helping to distinguish friendly cells from dangerous foreign invaders, or help construct miniature electronic circuits.

Whereas the nanobots of sci-fi nightmares are implausible little devices that mine atoms from the environment and use them to build more nano-brothers and sisters, von Kiedrowski's versions are based on the tried-and-tested molecular replicator DNA. Hisprototype replicators rely on the same principles that enable DNA to copy itself to pass on their own assembly instructions to a new generation. Why go to all the bother of designing replication systems from scratch, von Kiedrowski asks, when nature already has a good way of doing it?

That's not the only reason for nanotech scientists to seize on DNA's double helix. Over the past decade or so they have learnt that DNA is also the ideal construction material for nanoscale engineering. Usually building nanomachines is a fiddly and laborious task. But not if you can make the building blocks spontaneously join together in the desired arrangement, or self-assemble. And to do that, they need to be programmed with the right assembly instructions.

The discovery by Watson and Crick of the base-pairing mechanism that holds DNA's twin strands together showed that molecules can be imbued with information - which can then be used to organise themselves into sophisticated structures. In other words, DNA showed that chemistry can be seen as an information science. "The 1953 paper was the beginning of informed materials," says von Kiedrowski.

The information in DNA is carried as the sequence of chemical groups called bases, which project from the backbone of the strand. Pair each base with a "complementary" partner and a double helix can form. And thanks to advances in biotechnology that allow scientists to build their own DNA sequences to order, it's now possible to write entirely new messages into DNA molecules and so program them to join together in new ways. Nadrian Seeman at New York University has pioneered this approach to DNA-based molecular nanotechnology. He has built DNA strands that self-assemble into complicated shapes such as cubes and an interwoven mesh like chain mail.

Seeman uses "sticky-ended" DNA: short double helices where one strand is longer than the other, so that the unpaired bases dangle loose at the end. Another sticky-ended double helix can bind to it if the base sequences on the loose ends are complementary.

Last year, von Kiedrowski and his colleagues adapted this approach to create DNA nanostructures shaped like tetrahedra. The building blocks are three-armed molecules in which three single-stranded DNA molecules are attached to a central hub. Each of these "tripods" forms one of the corners of the tetrahedron. The arms of two tripods bind together to form a double helix when they have complementary sequences. The result is a robust nanostructure.

Admittedly this would make a pretty dull nanobot. But it's just a prototype. Structures made from DNA have been shown to be capable of a little more animation. Seeman, for example, has made a DNA assembly that can move like a tiny motor. Other researchers have created tweezers and pistons from DNA.

DNA can conduct electricity, so it is possible these nanostructures could be used to create tiny, self-assembling circuits. And the tiny machines could be assembled by radio control. Last year a team at the Massachusetts Institute of Technology showed that the pairing and unzipping of DNA strands can be controlled remotely by attaching gold nanoparticles to the strands. These act as antennas that pick up high-frequency radio waves, heating the assembly and unzipping the strands. Von Kiedrowski anticipates using this kind of mechanism to control nanobot construction.

When DNA replicates in cells, enzymes unzip the double helix and build two new strands, one base at a time, using the exposed single strand as a template. In the 1980s, Leslie Orgel of the Salk Institute in San Diego, California, found a way to copy short single strands without enzymes: individual base pairs could assemble on a template strand and link up into a complementary strand.

In general you can't make two identical strands from one in a single step, however, because the new strand is complementary to, not identical to, the template. But in 1986 von Kiedrowski realised that you could get around this by choosing to copy a sequence whose complementary sequence is identical to the original when read backwards. In this way his team demonstrated enzyme-free replication of a six-base strand of nucleic acid by using it as the template for assembling and linking together two three-base fragments.

Replication on a truly biological scale does not mean just making one copy - the replicator has to multiply exponentially. In practical terms, this means that the copy must separate from the template so both can act as templates for further copying. It's this rapid proliferation that makes nanoreplicators sound so fearsome. Von Kiedrowski was eventually able to show exponential proliferation of his six-base replicators.

But replication becomes more complicated when the template strand and complementary strand have different sequences. In that case you must first make a complementary strand, which then has to serve as the template for duplicating the original strand. In 1993, von Kiedrowski, and a team at the Scripps Research Institute in La Jolla, California, independently came up with a scheme for conducting this kind of replication. Two years later von Kiedrowski's group revealed a method that achieves exponential, enzyme-free replication of ordinary DNA, involving the attachment of the DNA strands to a surface in preparation for copying. They called this method SPREAD: Surface-Produced Replication and Exponential Amplification of DNA (see Graphic).

The researchers have now automated this procedure on a microchip. A DNA chain attached to one electrode of the microchip is used as the template to create a copy. This copy is chemically labelled with a charged end group so that when a voltage is applied across the chip, the copy unzips from the template and binds to the other electrode. The copy can then act as a new template.

Von Kiedrowski imagines using SPREAD to turn his DNA nanostructures into replicators. And last December, his team reported one of the crucial steps: copying the chemical information in the DNA tripods. To make sure that these tripods assemble into tetrahedra rather than other shapes, the researchers gave each arm a different sequence. They found that, when supplied with the three complementary strands to each arm, the tripods serve as templates, bringing these strands together so that they can be linked up into a new tripod. This produces a copy that is complementary to the first.

But researchers still have to intervene to keep the process going. They must supply the replicators with preformed DNA strands, and then separate the copy from the original. To achieve complete replication, via the SPREAD procedure say, will demand even more intervention. So there's no chance of the nanoscale tetrahedra becoming autonomous and multiplying spontaneously like viruses.

Despite the dire warnings voiced by some, global ecophagy isn't on the menu. It might make a good novel, but it's not good science. At least, not yet...

Philip Ball is a freelance writer and former associate editor at Nature

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