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Researchers at P&S and the University of New Mexico have built a device out of DNA molecules that beats all human challengers at tic-tac-toe, but don't expect to play DNA-based games in your cell phone any time soon.

The device, called MAYA, was designed by Dr. Milan Stojanovic, assistant professor in the Division of Clinical Pharmacology and Experimental Therapeutics at P&S, and Dr. Darko Stefanovic at New Mexico and represents the first time artificial DNA molecules have been assembled into circuits that can make complex decisions.

Milan Stojanovic (left) challenges his DNA automaton, MAYA, to tic-tac-toe. MAYA uses fluorescence to indicate its moves; the computer screen (right) shows MAYA has made its first move to the center.

These circuits, however, are not being designed to build a DNA-based computer of the future, and, in fact, the researchers say they doubt DNA can outcompete silicon processors.

Instead, they envision using the circuits in wet biological situations where electronic devices would short-circuit. Dr. Stojanovic's ultimate goal is to use the DNA-based circuits in microscopic drug delivery devices that can be introduced into the bloodstream, monitor changes in the body, and release a drug – insulin, for example – when needed.

"We're not going to make Game Boys out of this," Dr. Stojanovic says. "What we're showing is what kind of control these molecules can have in a practical application."

Tic-tac-toe was chosen as the application to solve since the decisions made during the game are relatively simple and, if played optimally, the first player will never lose. It's also a traditional challenge for computer scientists: Tic-tac-toe became the first computer game when in 1949 Cambridge scientists coded it on EDSAC, the first electronic computer to store programs.

The DNA-based "automaton," as the investigators prefer to call it, looks like no other tic-tac-toe game. On a lab bench, the nine test tubes comprising MAYA blend in with all the other scientific equipment.

But inside the nine tubes of MAYA are synthetic DNA enzymes that are responsible for guiding MAYA's every move.

Aside from its tic-tac-toe prowess, the researchers say MAYA behaves just like the enzymes in our own cells. "When you have a series of enzymes in a cell, the enzymes form a circuit. The cell uses these metabolic circuits to decide to eat, or move away from heat, or reproduce. It's all done through large assemblies of enzymes," Dr. Stojanovic says. "We have simply made a circuit of artificial enzymes that can play tic-tac-toe."

The artificial DNA enzymes that allow MAYA to make game decisions are designed to release a fluorescent molecule only when certain DNA fragments are present or absent. Combining several of these enzymes make up the circuits in MAYA that can analyze complex arrays of inputs to play tic-tac-toe.

The game starts when magnesium added to all nine tubes triggers MAYA to initiate the first move to the center of the board. The magnesium only interacts with the DNA enzyme in the center tube, unlocking a fluorescent molecule that marks the move.

The human player then decides where to make his or her first move and transmits this information to MAYA by adding a solution of DNA fragments to all the wells. A different set of DNA fragments exists for each location on the game board.

MAYA makes its second move after each tube analyzes the fragments. In one tube only, the fragments are able to unlock the fluorescent molecules from the tube's DNA enzymes, and the glow marks MAYA's decision.

By the human player's second move, MAYA has to take into account its own prior move and two human moves to come up with the best option. In the longest game, MAYA has to analyze four human moves.

Computational aspects of this work are funded by the National Science Foundation and health science aspects by NASA and NIH. Dr. Stojanovic also is a Searle Scholar.