An autonomous molecular computer for logical control of gene expression

Abstract

Early biomolecular computer research focused on laboratory-scale, human-operated computers for complex computational problems. Recently, simple molecular-scale autonomous programmable computers were demonstrated allowing both input and output information to be in molecular form. Such computers, using biological molecules as input data and biologically active molecules as outputs, could produce a system for 'logical' control of biological processes. Here we describe an autonomous biomolecular computer that, at least in vitro, logically analyses the levels of messenger RNA species, and in response produces a molecule capable of affecting levels of gene expression. The computer operates at a concentration of close to a trillion computers per microlitre and consists of three programmable modules: a computation module, that is, a stochastic molecular automaton; an input module, by which specific mRNA levels or point mutations regulate software molecule concentrations, and hence automaton transition probabilities; and an output module, capable of controlled release of a short single-stranded DNA molecule. This approach might be applied in vivo to biochemical sensing, genetic engineering and even medical diagnosis and treatment. As a proof of principle we programmed the computer to identify and analyse mRNA of disease-related genes associated with models of small-cell lung cancer and prostate cancer, and to produce a single-stranded DNA molecule modelled after an anticancer drug.

Thinking Outside the Silicon Box: Molecular AND Logic As an Additional Layer of Selectivity in Singlet Oxygen Generation for Photodynamic Therapy

“…9 RNA-based logic devices were also shown to be promising in vitro, yielding fluorescent proteins, 10 or potentially important DNA antisense drug sequences as outputs. 11 In this Communication, we will put forward the idea that in essence, a comparison between the silicon-based digital electronics and "chemical" logic gates is mostly unfair, chemical logic systems are inherently more capable than they are given credit for, and the potential of the chemical logic gates is yet largely untapped. The chemical logic gates and the biomolecules in living systems, including ourselves, speak the same language.…”

DNA biomolecular-electronic encoder and decoder devices constructed by multiplex biosensors

“…[12][13][14][15] In the decade since Adleman's invention, reports have been made of a wide and diverse range of DNA logic devices. [16][17][18][19][20][21][22] Winfree, Stojanovic, Willner, Katz and their co-workers have, for example, developed optically reported 'AND' , 'OR' and 'SET-RESET' logic gate operations. 7,[23][24][25][26][27][28][29][30][31] Although the above examples serve as promising proofs of principle (see also refs [27][28][29][30][31][32][33][34][35], it remains necessary to create complex, multicomponent devices on a single biomolecular platform to achieve increased computational complexity and develop realistic DNAbased information processing systems.…”

Molecular implementation of simple logic programs

“…(Who is Mortal?). This biomolecular computing system compares favourably with previous approaches in terms of expressive power, performance and precision 2,4,8,9,11,12,19 . A compiler translates facts, rules and queries into their molecular representations and subsequently operates a robotic system that assembles the logical deductions and delivers the result.…”

“…Autonomous programmable computing devices made of biomolecules could interact with a biological environment and be used in future biological and medical applications [1][2][3][4][5][6][7] . Biomolecular implementations of finite automata 8,9 and logic gates 4,[10][11][12][13] have already been developed [14][15][16][17][18] .…”