26.12.2001, 12:19 L solution at room room at solution L µ transitions per second 9 automata sharing the same systems are currently under 12 in vitro in 4484 Watt. Additional Additional Watt. -10 The BioSPI project is concerned with developing predictive Our molecular finite automaton has two states and it temperature at a combined rate of 10 construction in our laboratory and are on various stages of testing. Computing what molecules do models for molecular and biochemical processes. Such processes, carried out networks by of proteins, mediate the interaction of cells with their environment and are responsible Recently, cells. processing inside information the of most for of studies level system on focused been has interest much such networks, approaches and several been proposed have for their representation none of the and analysis. However, existing approaches fully integrates dynamics, molecular, and biochemical detail. software run independently and in parallel on inputs (which inputs on parallel in and software independently run could in principle be distinct) in 120 with transition fidelity greater than 99.8%, consuming less 10 than some are designated accepting states. Its software consists of transition rules, each specifying next a state based on the on positioned initially is It symbol. current the and state current transition each In state. initial the in leftmost symbol the input the machine one moves symbol to the right, changing its internal state according to one of the applicable transition rules. suspend it may Alternatively, without completing the computation if no transition rule applies. A computation terminates upon processing the last input symbol. An automaton is said to accept accepting an in terminates input this on computation a if input an final state. operates on binary strings of symbols. It solves computational problems autonomously. The hardware automaton’s consists of a restriction nuclease and ligase, the software and input are double-strandedencoded by DNA, programming amounts to and softwarechoosing appropriate molecules. Upon mixing solutions containing these components, the automaton processes the input molecule via a cascade restriction, of hybridization and that molecule output detectable a producing cycles, ligation encodes the final automaton’s state, and thus the computational result. In our implementation 10 972 8 934 Fax. 4506 [email protected] 972 8 934 Tel. E-mail: Department of Biological Chemistry and of Biological Chemistry Department and of Computer Science Department Applied Mathematics Molecules and Molecules computation systems with less-than-universal less-than-universal with systems 32 , communicating with their biochemical their with communicating , in vitro in in vivo in Medicine in 2050: “Doctor in a Cell” One such system that has already been successfully tested successfully been tested already has that One such system Autonomous biomolecular computers would in principle be Devices that convert information from one form into another computation capability. computation is a programmable finite automaton comprising DNA and DNA-manipulating enzymes (Fig. 2). A finite automaton is a notional computing machine that operates on finite sequences of symbols. The machine can be in one of a finite number of and state initial an designated is one which of states, internal environment via molecular input and output (Fig. 1). This ability research Our application. biomedical numerous in result might group aims to develop prototypes for such computers. are We developing currently Fig. 1 Fig. operate to able operating autonomously on the molecular scale remain rare. Computing with molucles with Computing according to a definite procedure are known as automata. One such hypothetical device is the machine, universal Turing which stimulated work leading to the development of modern cases, including special its and machine Turing computers. The finite automata, operate scanning by a data tape, whose information-encoding inspired biopolymers to analogy striking several designs for molecular DNA computers. Laboratory-scale computing using DNA and human-assisted protocols has been demonstrated, but the attempts to realize computing devices Rivka Adar Benenson Kobi Gregory Linshitz Aviv Regev William Silverman Ehud Shapiro Ehud

]32 ehud_shapiro ehud_shapiro context. cellular awider in and clock the within module hysteresis ofthe function the establish and system, ofthe behavior the atcapturing good areequally ofdescription levels both that weshow programs, BioSPI two using By module. functional this using system the described -and module -ahysteresis system the in module afunctional weidentified Second, explicitly. interactions molecular the wemodeled First, of abstraction. structures, we investigated at levels two the machinery circadian modular tocapture calculus ofthe ability the Using clock. system to study a recently proposed model of the circadian BioSPI We the have systems. used ofbiological design modular levels of complexity. This is instrumental for studying the different between alternation and networks ofcomplex modeling networks. biochemical of simulation and forrepresentation BioSPI, called system, computer anew wedeveloped model, this on Based reactions. biochemical corresponding ofthe rates tothe according rates areassigned actions where spi-calculus, the variant, stochastic quantitative networks, modeling of we biochemical employ a remaining faithful biologically and transparent. To allow accurate are processes biochemical mathematically well defined, while model, Inour processes. computer distributed for describing developed originally algebra aprocess pi-calculus, the using fig.2 The modular nature of the calculus allows incremental incremental allows calculus ofthe nature modular The processes for biochemical models We predictive develop Design details and mechanism of operation of the molecular finite automaton finite molecular the of operation of mechanism and details Design 33 Selected Publications compartmentalization. and localization interaction, for molecular framework modular afuller toprovide system, BioSPI ofthe part as calculus adapted the toincorporate We intend compartments. ofcellular rearrangement dynamic and compartments between ofmolecules movement the including compartmentalization, and localization molecular of aspects various represent For additional information see: information For additional MINERVA the and foundetion. Research forBiomedical Center Ebner Lola and Dolphi the from Cambridge, Research, Microsoft from Cardelli Luca and of Verona, Italy UK. This workBarkai is supported from the by Weizmann aAcknowledgements research Institute, grant Corrado Priami from U. Y.,Benenson, Paz-Elizur, T., Adar, E., Livneh, Keinan, R., We are currently extending our modular framework to framework modular our extending We arecurrently www.wisdom.weizmann.ac.il/~udi Tamar Livneh, Zvi Naama Paz-Elizur and with We collaborate 430-434. computing machine made of biomolecules. Nature, 414, Shapiro,Z. E. (2001) Programmable and autonomous

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