There's rarely time to write about every cool science story that comes our way. So this year, we're running a special Twelve Days of Christmas series of posts, highlighting one story that fell through the cracks each day, from December 25 through January 5. Today: Playing tic-tac-toe with DNA origami.

Scientists at Caltech have created the world's smallest game board for playing tic-tac-toe out of DNA strands. What's more, it's possible to swap hundreds of DNA strands in and out at once to reconfigure the nanostructure at will, making it possible in principle to build complicated nanomachines in different custom patterns. The scientists described their work in a December paper in Nature Communications.

Back in 2006, Caltech bioengineer Paul Rothemund figured out how to fold a long strand of DNA into simple shapes, demonstrating this "DNA origami" technique by producing a smiley face. All you need is a long strand of DNA, plus several shorter strands ("staples"). Combine them in a test tube, and the shorter strands pull various parts of the long strand together so that it folds over into any number of simple shapes. DNA origami was a huge advance for nanotechnology, but to really achieve its full potential, scientists needed to be able to create larger and more complex structures.

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Last year, Rothemund's Caltech colleague Lulu Qian introduced a cheap means of getting DNA origami to assemble itself into large arrays. The best part: you could create custom patterns. The array was a bit like a blank canvas, and Qian demonstrated the power of her technique (dubbed "fractal assembly") by creating the world's smallest version of Leonardo da Vinci's "Mona Lisa," visible only with atomic force microscopy.

A jigsaw puzzle

DNA strands are made up of four types of base molecules: adenine, cytosine, guanine, and thymine (A, C, G, and T) that can be arranged in any order. Those molecules also like to pair up with their respective complements: A with T, and C with G. Any sequence of bases will naturally self-assemble with a complementary sequence—ATTAGCA, for instance, will pair with TAATCGT.

Qian's method exploits that natural tendency to create self-assembling tiles that can be arranged into custom patterns, like the "Mona Lisa." While the DNA tiles are all shaped like a square, each one only fits in a particular spot. You can recreate Leonardo's masterpiece, or get the DNA tiles to self-assemble into any number of intricate patterns.

Qian et al. started out by taking an image of the "Mona Lisa" and using software to divide it into small spare-shaped sections. Then they figured out which DNA sequences they would need to make up those squares. The biggest challenge was figuring out how to get the DNA tiles to assemble themselves into an overall "Mona Lisa" pattern. They decided to approach the problem in stages via a series of "mini puzzles," putting together small regions first, and them assembling those into larger regions, before putting it all together for the final product.


There was just one catch: once you used fractal assembly to create a pattern, you really couldn't change it. Qian's latest achievement combines the self-assembly with a new technique called strand displacement. DNA sequences can also pair up with a partially matching sequence. For example, if you had ATTAGCA and TAATACC strands, the ATTA and TAAT portions would pair up, leaving the GCA and ACC parts dangling at the ends. The DNA tiles can be tailored in such a way that they can find their designated spot on the game board and kick out whatever tile is already there. And they can do this with multiple tiles at once.

To illustrate the concept of strand displacement, Qian et al, draw a simple analogy to two people, Amy and Adam, who have a few things in common and decide to date. Then a third person, Eddie comes along. Amy discovers she has three things in common with Eddie, compared to two with Adam, so heartless Amy ditches poor Adam for Eddie. (You can visualize this with your own preferred romantic triangle configuration.) Adam is like the displaced DNA strand, left hanging and partner-less.

To create their game of tic-tac-toe, Qian et al. mixed up a solution of blank tiles in a test tube and let it self-assemble into a game board. Then the "players" took turns adding either custom tailored X tiles or O tiles to the test tube, which would replace the blank tiles already in those positions. Per the Caltech press release, "After six days of riveting gameplay, player X emerged victorious." (It declined to identify player X.)

Of course, playing tic-tac-toe is just a handy way to demonstrate the technique. The true benefit lies in enabling bioengineers to build more complicated and sophisticated nano machines that can be reconfigured at will. "When you get a flat tire, you will likely just replace it instead of buying a new car. Such a manual repair is not possible for nanoscale machines," said co-author Grigory Tikhomirov. "But with this tile displacement process we discovered, it becomes possible to replace and upgrade multiple parts of engineered nanoscale machines to make them more efficient and sophisticated."


DOI: Nature Communications, 2018. 10.1038/s41467-018-07805-7 (About DOIs).

Listing image by Qian Lab/Caltech