> ## Time to Engineer DNA Computers

> By R. Colin Johnson
> EE Times
> January 3, 2001 (3:43 p.m. ET)

> Leonard Adleman, the man who invented the "DNA computer," claims that the riches lie along the side of the road rather than at the end of the rainbow. Engineers working toward replacing computers with molecular-sized DNA machinery, he said, will discover ways to use DNA for all manner of applications, and those discoveries will overshadow their progress toward developing a true DNA computer.

> "I don't expect that we will ever have a PC that's a DNA computer, for instance, but we will be able to do things with DNA that we can't with any other type of technology," said Adleman, a professor at the University of Southern California.

> The amazing density of DNA as an information storage medium-a single cubic centimeter of DNA holds more information than a trillion CDs-prompted Adleman's first demonstration, in 1994, that DNA molecules could solve computational problems. He used strips of DNA like the tape in a Turing machine, and performed read and write operations with the tools of genetic engineering. In 2000, Adleman upped the ante by using more modern genetic engineering techniques to solve a six-variable problem, albeit one that some humans could solve by hand. His next milestone, slated for 2002, is a 20-variable problem that any human being would find daunting.

> "'These demonstrations are to show people how DNA can be directed to process information in very specific ways, but I think others will think of much cooler applications," Adleman said.

> DNA computers work by encoding the problem to be solved in the language of DNA: the base-four values A, T, C and G. Using this base-four number system, the solution to any conceivable problem can be encoded along a DNA strand a la a Turing machine tape. Every possible sequence can be chemically created in a test tube on trillions of different DNA strands, and the correct sequences can be filtered out using genetic engineering tools.

> This massive process-of-elimination method of finding solutions to problems, a kind of Darwinian survival of the fittest at the molecular level, has evolved to become the universal method of storing and processing information in living things. Plants, animals, humans, bacteria, viruses-literally all living things use DNA to store and process the biological information that directs the processes of life. The density of this information is enormous, scaling all the way up to the history of an entire species and scaling down to individual molecules. DNA is essentially godlike in that it "remembers" the history of a species, from single cells to higher animals.

> "We have in our hands the legacy from about 3 billion years of evolution, which we have never been able to tap into before now. DNA's legacy is the machinery inside the living cell," Adleman explained.

> Leonard Adleman envisions much more sophisticated DNA computer uses than today's apps offer because of the tools we find in a living cell.

> Since Watson and Crick started the molecular biology revolution in the 1950s, culminating in cataloging the human genome, thousands of commercial tools have been created and marketed for manipulating molecules. Those chemicals have been used mostly for biological purposes like creating new drugs, but Adleman said he envisions them enabling a new wave of applications that use these tiny molecular building blocks for information processing, just as he does in his demonstration studies.

> "What you find inside the cell are an incredible number of molecules. Some of them act like little motors, some of them store information like DNA, some transmit energy and many, many other things-there are literally tens of thousands of different molecules in different cells-and these make up a new tool box for the third-millennium engineer," Adleman said.

> The real challenge, according to Adleman, is what engineers will build with these wonderful new tools. For instance, there is a molecule inside the cell that measures only 4 nanometers square but which can autonomously travel down a strand of DNA reading each A, T, C and G base, creating a Watson-Crick complementary strand of DNA from free-floating bases in solution and then releasing that copy. Adleman doesn't claim to know how engineers will use this molecule specifically, but he envisions applications that are orders of magnitude more sophisticated than today's apps.

> Microelectromechanical system (MEMS) researchers "will never be able to create molecular machinery as sophisticated as the tools inside the living cell," Adleman said. "We only have access to such sophisticated tools because of 3 billion years of evolution."

> Other active tools developments have given engineers at the molecular level perform operations like those of a motor, or a scissors, or a splicer, or a duplicator or many much finer and more precise operations for specialized purposes. By learning to direct the activities of these molecular tools that already exist, engineers will be able to create product seeds that grow into the desired product when given proper nourishment.

> In addition to being as complex as living things, these tools also operate orders of magnitude more efficiently than the crude tools of MEMS. In fact, all molecular operations inside the cell perform at the very edge of thermodynamic feasibility, thereby operating at nearly 100 percent efficiency-something MEMS devices will never approach, according to Adleman.

> "It is very hard to specify just what we will be building with these elegant new tools; the DNA computer is more or less a demonstration of the robustness of these kind of tools to solve information-processing problems. But if you can build a computer, then what other useful devices could you build on that very small scale? The possibilities are endless," Adleman said.

> Besides all the obvious nanotechnology applications, such as smart pills, Adleman suggested that the molecular precision of DNA tools could be used to pattern polysilicon directly without lithography. Building ultimately dense chips with atomic precision is already being done in research labs using DNA as the basic material to pattern chip substrates, Adleman said. By laying grids of DNA very precisely atop silicon substrates, unbelievably dense patterns of nanocrystals can seed polysilicon circuits fabricated atop them, according to Adleman.

> Molecular buildup

> "At the molecular scale, DNA can lay down patterns with 5-nm accuracy, enabling circuits to be built up on a chip from the bottom up-molecule by molecule-rather than with bulk deposition and lithography," Adleman said.

> Those substrates, he contends, would pattern themselves using molecular machines that self-assemble ultimately dense circuitry patterns onto flat sheets with atomic precision. The sheets could then be used to direct the placement of polysilicon materials atop them, making up the actual circuit elements.

> Adleman suggests that engineers get a broad-based science education that specializes in nothing, save mathematics, Adleman's own degree. "We are no longer interested in using the tools of biology to study biology but to create a new generation of devices. For engineers, it will require an understanding of both biology and electronics," Adleman said. "I see the resurgence of the scientific generalist- researchers who have a broad base in mathematics, physics, chemistry, biology and computer science but are here to invent something new."

> According to Adleman, mathematics gives engineers the ability to analyze and think about the different aspects of problems, even when there is no particular problem under consideration. If you understand mathematics, the only difference between physics and biology is just plugging in a different data set, he said.

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