Fast, rewritable computing with DNA origami registers

DNA stores the instructions for life and, along with enzymes and other molecules, computes everything from hair color to risk of developing diseases. Harnessing that prowess and immense storage capacity could lead to DNA-based computers that are faster and smaller than today’s silicon-based versions. As a step toward that goal, researchers report in ACS Central Science a fast, sequential DNA computing method that is also rewritable — just like current computers.

“DNA computing as a liquid computing paradigm has unique application scenarios and offers the potential for massive data storage and processing of digital files stored in DNA,” says Fei Wang, a co-author of the study.

In living organisms, DNA expression occurs sequentially: Genes are transcribed into RNA, which is translated into proteins. This process happens to many genes simultaneously and repeatedly. If researchers can duplicate this complex, elegant dance in DNA-based computers, these devices could be more powerful than current silicon-based machines. Researchers have demonstrated sequential DNA computing for very focused, specialized tasks. But until recently, not much progress had been made in developing more general and programmable DNA devices that could be used and reused for various applications.

In previous research, Chunhai Fan, Wang and colleagues developed a programmable DNA integrated circuit with many logic gates that act as instructions for the circuit’s operations. Here’s how it worked:

• Data, 0 or 1, was represented by a short piece of single-stranded DNA, called an oligonucleotide, that contained a series of bases: adenine, thymine, guanine and cytosine. (In nature, the sequence of bases codes for a gene.)
• For example, two inputs of 1 (DNA strands 1 and 2) would interact with an OR logic gate DNA molecule.
• Then in a fluid-filled tube, the input oligonucleotide interacted with a logic gate DNA molecule and generated an output oligonucleotide.

• The output oligonucleotide bound to a different single-stranded DNA that was folded into an origami-like structure, called a register in computer lingo.

• The oligonucleotide was “read” by reviewing its base sequence, released and used in a vial containing the next gate, and so on.

This process took hours, and someone had to manually transfer the oligonucleotide from one gate to another vial for the next computing operation. So the team, along with Hui Lv and Sisi Jia, wanted to speed things up.

To make the reaction processes more efficient and compact, the team first placed the DNA origami register onto a solid glass 2D surface. The output oligonucleotide floating in liquid from a specific logic gate then attached to the glass-mounted register. After the output oligonucleotide was read and the logic gate instructions determined, it detached, which reset the register so it could be rewritten, thereby avoiding the need to move or replace registers. The researchers also designed an amplifier that boosted the output signal so all the pieces — the gates, oligonucleotides and registers — could find one another more easily. In a proof-of-concept experiment, all the DNA computing reactions took place in a single tube within 90 minutes.

“This research paves the way for developing large-scale DNA computing circuits with high speed and lays the foundation for visual debugging and automated execution of DNA molecular algorithms,” says Wang.

The authors acknowledge funding from the National Key Technologies R&D Program, the National Natural Science Foundation of China, the Science Foundation of Shanghai Municipal Commission of Science and Technology, the China Postdoctoral Science Foundation, the New Cornerstone Science Foundation, and the K.C. Wong Education Foundation.

The paper’s abstract will be available on Dec. 11 at 8 a.m. Eastern time here: http://pubs.acs.org/doi/abs/10.1021/acscentsci.4c01557     

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