Biocomputing Advance Presages Logic Control over Biochemical Processes

Building these circuits allows researchers from Caltech to study the principles of computing with biologic 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. For example, a synthetic biochemical circuit could be introduced into a clinical blood sample to detect the levels of a variety of molecules in the sample, and integrate that information into a diagnosis of any possible 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," said Dr. Lulu Qian, a senior postdoctoral scholar in bioengineering at Caltech and lead author on a paper published in the June 3, 2011, issue of the journal Science.

Along with Dr. Erik Winfree, Caltech professor of computer science, computation, and neural systems, and bioengineering, Dr. Qian utilized a new type of DNA-based component to build the largest artificial biochemical circuit ever made. Earlier lab-made biochemical circuits were limited because they worked less reliably and predictably when scaled to larger sizes, Dr. Qian explained. The most probable reason behind this limitation is that such circuits require various molecular structures to implement different functions, making large systems more complicated and difficult to debug. The researchers' new application, however, involves components that are simple, standardized, effective, and scalable.

"You can imagine that in the computer industry, you want to make better and better computers," Dr. Qian said. "This is our effort to do the same. We want to make better and better biochemical circuits that can do more sophisticated tasks, driving molecular devices to act on their environment."

To construct their circuits, the researchers used pieces of DNA to make logic gates--devices that produce on-off output signals in response to on-off input signals. Biochemical circuits comprise molecules floating in salt water. 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.

Dr. Winfree and his colleagues first built such a biochemical circuit in 2006. In this work, DNA signal molecules connected several DNA logic gates to each other, forming a multilayered circuit. However, this earlier circuit consisted of only 12 different DNA molecules, and the circuit slowed down by a few orders of magnitude when expanded from a single logic gate to a five-layered circuit. In their new design, the researchers have engineered logic gates that are simpler and more reliable, allowing them to make circuits at least five times larger.

The 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.

"The molecules are just floating around in solution, bumping into each other from time to time," Dr. Winfree explained. "Occasionally, an incoming strand with the right DNA sequence will zip itself up to one strand while simultaneously unzipping another, releasing it into solution and allowing it to react with yet another strand." Because the researchers can encode whatever DNA sequence they want, they have full control over this process. "You have this programmable interaction," he commented.

Drs. 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 (essentially, a 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 will not replace a PC anytime soon. However, the purpose of these circuits is not to compete with electronics, but to give scientists logic control over biochemical processes.

All the logic gates have identical structures with different sequences. As a result, they can be standardized, so that the same types of components can be wired together to make different circuits. Moreover, according to Dr. Qian, the user does not have to know anything about the molecular machinery behind the circuit to make one. If you want a circuit that could automatically diagnoses a disease, one just submits an abstract representation of the logic functions in your design to a compiler that the researchers provide online, which will then translate the design into the DNA components needed to build the circuit.

The circuit components are also tunable. By adjusting the concentrations of the types of DNA, the researchers can alter the functions of the logic gates. The circuits are versatile, featuring plug-and-play components that can be easily reconfigured to rewire the circuit. The simplicity of the logic gates also allows for efficient techniques that synthesize them in parallel.

"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," Dr. Winfree says.

Dr. Qian added, "The dream is that synthetic biochemical circuits will one day achieve complexities comparable to life itself."

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