Caltech professor Erik Winfree, who with colleague Paul W.K. Rothemund won the 2006 Feynman Prizes in Nanotechnology for both the experimental work and theory categories, and postdoctoral researcher Lulu Qian have designed a simple DNA gate architecture practical for the construction of large-scale circuits that could eventually involve thousands of gates. Such complex biochemical circuits, although very slow compared to current electronic computers, could be appropriate for the embedded control of molecular devices. “A simple DNA gate motif for synthesizing large-scale circuits” was published in the Journal of the Royal Society Interface and is available free. As described on their web site, the authors call these DNA nanotechnology devices “seesaw gates”. Back-and-forth strand displacements enable the systematic design of computing networks:
…Remarkably, the ebb and flow of activity in these networks can perform computations of arbitrary complexity in principle — in fact, we describe a compiler that translates digital logic circuits into functionally equivalent seesaw gate networks, and we argue that the simplicity of the motif should make networks containing thousands of gates possible. If this theoretical proposal pans out experimentally, could it become a core technology for embedding circuitry in synthetic biochemical systems?
A recent experimental implementation is described in a Caltech news release written by Marcus Woo “Caltech Researchers Build Largest Biochemical Circuit Out of Small Synthetic DNA Molecules“:
In many ways, life is like a computer. An organism’s genome is the software that tells the cellular and molecular machinery—the hardware—what to do. But instead of electronic circuitry, life relies on biochemical circuitry—complex networks of reactions and pathways that enable organisms to function. Now, researchers at the California Institute of Technology (Caltech) have built the most complex biochemical circuit ever created from scratch, made with DNA-based devices in a test tube that are analogous to the electronic transistors on a computer chip.
Engineering these circuits allows researchers to explore the principles of information processing in biological systems, and to design biochemical pathways with decision-making capabilities. Such circuits would give biochemists unprecedented control in designing chemical reactions for applications in biological and chemical engineering and industries. For example, in the future a synthetic biochemical circuit could be introduced into a clinical blood sample, detect the levels of a variety of molecules in the sample, and integrate that information into a diagnosis of the pathology.
“We’re trying to borrow the ideas that have had huge success in the electronic world, such as abstract representations of computing operations, programming languages, and compilers, and apply them to the biomolecular world,” says Lulu Qian, a senior postdoctoral scholar in bioengineering at Caltech and lead author on a paper published in the June 3 issue of the journal Science. [“Scaling Up Digital Circuit Computation with DNA Strand Displacement Cascades” abstract]
Along with Erik Winfree, Caltech professor of computer science, computation and neural systems, and bioengineering, Qian used a new kind of DNA-based component to build the largest artificial biochemical circuit ever made. … The researchers’ new approach … involves components that are simple, standardized, reliable, and scalable, meaning that even bigger and more complex circuits can be made and still work reliably. …
To build their circuits, the researchers used pieces of DNA to make so-called logic gates—devices that produce on-off output signals in response to on-off input signals. … Instead of depending on electrons flowing in and out of transistors, DNA-based logic gates receive and produce molecules as signals. The molecular signals travel from one specific gate to another, connecting the circuit as if they were wires. …
Their new logic gates are made from pieces of either short, single-stranded DNA or partially double-stranded DNA in which single strands stick out like tails from the DNA’s double helix. The single-stranded DNA molecules act as input and output signals that interact with the partially double-stranded ones. …
Qian and Winfree made several circuits with their approach, but the largest—containing 74 different DNA molecules—can compute the square root of any number up to 15 (technically speaking, any four-bit binary number) and round down the answer to the nearest integer. The researchers then monitor the concentrations of output molecules during the calculations to determine the answer. The calculation takes about 10 hours, so it won’t replace your laptop anytime soon. But the purpose of these circuits isn’t to compete with electronics; it’s to give scientists logical control over biochemical processes. …
Because the logic gates have identical structures, they can be standardized and wired together to make any desired circuit. The authors have provided an online compiler (with a source code that can be downloaded) to give the DNA sequences for any digital circuit.
“Like Moore’s Law for silicon electronics, which says that computers are growing exponentially smaller and more powerful every year, molecular systems developed with DNA nanotechnology have been doubling in size roughly every three years,” Winfree says. Qian adds, “The dream is that synthetic biochemical circuits will one day achieve complexities comparable to life itself.”
The authors have explained their process with a delightful YouTube video, The Seesaw Magic Book. Among the several informative commentaries on this research is “DNA logic gates calculate square root using 130 different molecules” by John Timmer:
… Still, it does have its appeal. Various biomolecules, including DNA, RNA, enzymes, and small molecules, could all potentially be used as inputs. And it should be possible to link the outputs into relevant biological functions, including gene expression. Finally, the authors have a rather clever idea to speed things up. Instead of having all the gates floating loose in a test tube, they suggest that it might be possible to use large DNA scaffolds to assemble gates in close proximity to each other, ensuring that reactions take place quickly and require far less DNA to be used.
