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.

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. Previous lab-made biochemical circuits were limited because they worked less reliably and predictably when scaled to larger sizes, Qian explains. The likely reason behind this limitation is that such circuits need various molecular structures to implement different functions, making large systems more complicated and difficult to debug. The researchers' new approach, however, involves components that are simple, standardized, reliable, and scalable, meaning that even bigger and more complex circuits can be made and still work reliably.

"You can imagine that in the computer industry, you want to make better and better computers," Qian says. "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 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. Logic gates are the building blocks of the digital logic circuits that allow a computer to perform the right actions at the right time. In a conventional computer, logic gates are made with electronic transistors, which are wired together to form circuits on a silicon chip. Biochemical circuits, however, consist of molecules floating in a test tube of salt water. 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.