DNA Computers for Work and Play

INFORMATION SCIENCE COMPUTERS DNA FOR WORK AND PL AY TIC-TAC-TOE-PLAYING COMPUTER consisting of DNA strands in solution demonstrates the potential of molecular logic gates. © 2008 SCIENTIFIC AMERICAN, INC. Logic gates made of DNA could one day operate in your bloodstream, collectively making medical decisions and taking action. For now, they play a mean game of in vitro tic-tac-toe By Joanne Macdonald, Darko Stefanovic and Milan N. Stojanovic rom a modern chemist’s perspective, the mentary school in Belgrade, Serbia, we hap- structure of DNA in our genes is rather pened to be having dinner, and, encouraged by Fmundane. The molecule has a well-known some wine, we considered several topics, includ- importance for life, but chemists often see only ing bioinformatics and various existing ways of a uniform double helix with almost no function- using DNA to perform computations. We decid- al behavior on its own. It may come as a surprise, ed to develop a new method to employ molecules then, to learn that this molecule is the basis of a to compute and make decisions on their own. truly rich and strange research area that bridges We planned to borrow an approach from synthetic chemistry, enzymology, structural electrical engineering and create a set of molec- nanotechnology and computer science. ular modules, or primitives, that would perform Using this new science, we have constructed elementary computing operations. In electrical molecular versions of logic gates that can oper- engineering the computing primitives are called ate in water solution. Our goal in building these logic gates, with intuitive names such as AND, DNA-based computing modules is to develop OR and NOT. These gates receive incoming nanoscopic machines that could exist in living electrical signals that represent the 0s and 1s of organisms, sensing conditions and making deci- binary code and perform logic operations to sions based on what they sense, then responding produce outgoing electrical signals. For instance, with actions such as releasing medicine or kill- an AND gate produces an output 1 only if its ing specific cells. two incoming inputs are both 1. Modern-day We have demonstrated some of the abilities of computers have hundreds of millions of such KEY CONCEPTS our DNA gates by building automata that play logic gates connected into very complex circuits, n DNA molecules can act perfect games of tic-tac-toe. The human player like elaborate structures built out of just a few as elementary logic gates adds solutions of DNA strands to signal his or kinds of Lego blocks. Similarly, we hoped that analogous to the silicon- her moves, and the DNA computer responds by our molecular modules could be mixed together based gates of ordinary lighting up the square it has chosen to take next. into increasingly complex computing devices. computers. Short strands Any mistake by the human player will be pun- We did not aim, however, to compete with sil- of DNA serve as the gates’ ished with defeat. Although game playing is a icon-based computers. Instead, because Sto- inputs and outputs. long way from our ultimate goals, it is a good janovic had just finished a brief stint with a phar- n Ultimately, such gates test of how readily the elementary molecular maceutical company, we settled on developing a could serve as dissolved computing modules can be combined in plug- system that could be useful for making “smart” “doctors”—sensing mole- and-play fashion to perform complicated func- therapeutic agents, such as drugs that could sense cules such as markers on tions, just as the silicon-based gates in modern and analyze conditions in a patient and respond cells and jointly choosing computers can be wired up to form the complex appropriately with no human intervention after how to respond. logic circuits that carry out everything that com- being injected. For example, one such smart n Automata built from these puters do for us today. agent might monitor glucose levels in the blood DNA gates demonstrate and decide when to release insulin. Thus, our the system’s computation- Dissolved Doctors molecular logic gates had to be biocompatible. al abilities by playing Near the end of 1997 two of us (Stojanovic and Such molecular modules could have innumer- an unbeatable game of Stefanovic) decided to combine our individual able functions. For instance, in diseases such as tic-tac-toe. skills in chemistry and computer science and leukemia, numerous subpopulations of white —The Editors JEAN-FRANCOIS PODEVINJEAN-FRANCOIS work on a project together. As friends from ele- blood cells in the immune system display char- www.SciAm.com © 2008 SCIENTIFIC AMERICAN, INC. SCIENTIFIC AMERICAN 85 acteristic markers on their cell surfaces, depend- very analogous to the workings of silicon logic ing on the cells’ lineage and their stage of devel- OTHER DNA gates. Nevertheless, DNA clearly had a lot of po- opment. Present-day therapies using antibodies COMPUTERS tential for biocompatible computation, and a eliminate large numbers of these subpopulations couple of other advances gave us the tools to in- Researchers over the years at once, because they target only one of the sur- have devised several ways to vent our own brand of DNA logic gates. face markers. Such indiscriminate attacks can perform computations by First, in 1995 Gerald F. Joyce of the Scripps suppress the patient’s immune system by wiping exploiting DNA’s ability Research Institute in La Jolla, Calif., developed out too many healthy cells, leading to serious to store information in its a method for producing enzymes made out of sin- complications and even death. Molecular mod- sequence of bases. gle strands of DNA that cut other pieces of sin- ules capable of working together to sense and gle-stranded DNA into two segments. These so- 1994: Leonard M. Adleman — analyze multiple markers including perform- of the University of Southern called deoxyribozymes have two short arms that ing logical operations such as “markers A and California solved a puzzle will bind only to another stretch of DNA that has either B or C are present, but D is absent”— known as the Hamiltonian path the correct complementary sequence of bases, so might be able to select the specific subpopula- problem by encoding all the they are very specific about which substrate DNA tions of cells that are diseased and growing out possible solutions (both correct strands they will cleave [see box on page 88]. and incorrect) on a large num- of control and then eliminate only those cells. ber of DNA molecules and Special dye molecules attached to each end of Another application of our modules could be carrying out a series of steps to the substrate strands enable laboratory workers in the analysis of DNA, looking for a large array isolate the molecules with the to monitor the cleaving process. At one end of of possible genetic mutations or identifying one correct solution [see “Comput- the substrate, the dye molecule is a “quencher,” of a wide variety of microbiological pathogens. ing with DNA,” by Leonard M. which prevents the fluorescent marker dye at the Adleman; SCIENTIFIC AMERIC A N , Our most advanced tic-tac-toe-playing automa- August 1998]. other end from fluorescing as long as the strand ton combines 32 different short DNA sequences remains intact, keeping the quencher close (oligonucleotides). That many logic gate inputs 1995: Erik Winfree, now at the enough to be effective. After the strand is cut, its could analyze four billion possible combinations California Institute of Technolo- two pieces move apart and the marker dye mol- of oligonucleotides and partition them into thou- gy, proposed that tiles made ecule can fluoresce unhindered. As the work of sands of patterns, each pattern being character- of DNA could be designed to the DNA enzymes progresses, cutting more and perform computations by self- istic of certain pathogens or genotypes. assembling into two-dimension- more strands, the solution gradually lights up al structures [see “Nano- with the marker dye’s fluorescent color. Molecular Logic technology and the Double The other key advance came soon after our Researchers reported logic gates based on syn- Helix,” by Nadrian C. Seeman; initial planning, when Ronald R. Breaker of Yale thetic molecules as long ago as the early 1990s. SCIENTIFIC AMERIC A N , June 2004]. University reported a way to integrate a deoxyri- In 1993, for instance, A. Prasanna de Silva and bozyme with molecular groups acting as recog- 2004: Ehud Shapiro of the his collaborators at Queen’s University Belfast Weizmann Institute of Science nition modules. These modules work like sensors made AND gates out of small organic molecules in Rehovot, Israel, and Yaakov that either activate or inhibit their attached DNA that would fluoresce only if both hydrogen ions Benenson of Harvard Universi- enzyme when the correct input molecule is bound (from acid) and sodium ions were bound to ty, building on a proposal by to them. Breaker even combined two such mod- them. In 1997 J. Fraser Stoddart, now at North- Paul W. K. Rothemund of ules in a construct that could serve as an AND Caltech, developed a “doctor in western University, and his co-workers made a cell.” Enzymes operating on gate with two small input molecules. Very in- “exclusive OR” (XOR) gates, in which the mol- DNA analyzed whether a com- triguingly, his group has found that such two- ecules fluoresced in the presence of either, but bination of RNA molecules sensor constructs have been used by natural ri- not both, of the inputs (in this case, hydrogen indicative of a disease was boswitches—molecules made of RNA used by ions and molecules called amines).

Load more