Noise-aided computation within a synthetic gene network through morphable and robust logic gates.

An important goal for synthetic biology is to build robust and tunable genetic regulatory networks that are capable of performing assigned operations, usually in the presence of noise. In this work, a synthetic gene network derived from the bacteriophage λ underpins a reconfigurable logic gate wherein we exploit noise and nonlinearity through the application of the logical stochastic resonance paradigm. This biological logic gate can emulate or "morph" the AND and OR operations through varying internal system parameters in a noisy background. Such genetic circuits can afford intriguing possibilities in the realization of engineered genetic networks in which the actual function of the gate can be changed after the network has been built, via an external control parameter. In this article, the full system characterization is reported, with the logic gate performance studied in the presence of external and internal noise. The robustness of the gate, to noise, is studied and illustrated through numerical simulations.

[1]  Julien F. Ollivier,et al.  Colored extrinsic fluctuations and stochastic gene expression , 2008, Molecular systems biology.

[2]  C. Bashor,et al.  References and Notes Supporting Online Material Using Engineered Scaffold Interactions to Reshape Map Kinase Pathway Signaling Dynamics , 2022 .

[3]  R. Murenzi Science is helping Rwanda give up the ghosts of the past , 2008, Nature.

[4]  David A. Drubin,et al.  Rational design of memory in eukaryotic cells. , 2007, Genes & development.

[5]  F R Adler,et al.  How to make a biological switch. , 2000, Journal of theoretical biology.

[6]  C. Gardiner Handbook of Stochastic Methods , 1983 .

[7]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[8]  H. Risken The Fokker-Planck equation : methods of solution and applications , 1985 .

[9]  A. Kierzek,et al.  The Effect of Transcription and Translation Initiation Frequencies on the Stochastic Fluctuations in Prokaryotic Gene Expression* , 2001, The Journal of Biological Chemistry.

[10]  Ron Weiss,et al.  A molecular noise generator , 2008, Physical biology.

[11]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[12]  Farren J. Isaacs,et al.  Prediction and measurement of an autoregulatory genetic module , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Mark Ptashne,et al.  λ Repressor and cro—components of an efficient molecular switch , 1981, Nature.

[14]  J. Hasty,et al.  Noise-based switches and amplifiers for gene expression. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D. Endy,et al.  Refinement and standardization of synthetic biological parts and devices , 2008, Nature Biotechnology.

[16]  P. R. ten Wolde,et al.  DNA looping provides stability and robustness to the bacteriophage λ switch , 2009, Proceedings of the National Academy of Sciences.

[17]  Mads Kaern,et al.  The engineering of gene regulatory networks. , 2003, Annual review of biomedical engineering.

[18]  Adi R. Bulsara,et al.  Tuning in to Noise , 1996 .

[19]  P ? ? ? ? ? ? ? % ? ? ? ? , 1991 .

[20]  J. Collins,et al.  DIVERSITY-BASED, MODEL-GUIDED CONSTRUCTION OF SYNTHETIC GENE NETWORKS WITH PREDICTED FUNCTIONS , 2009, Nature Biotechnology.

[21]  M. Ptashne A genetic switch : phage λ and higher organisms , 1992 .

[22]  R. D. Boss,et al.  Noise effects in an electronic model of a single neuron , 1989, Biological Cybernetics.

[23]  Adi R. Bulsara,et al.  Logical stochastic resonance , 2010 .

[24]  P. Swain,et al.  Stochastic Gene Expression in a Single Cell , 2002, Science.

[25]  R. Weiss,et al.  Ultrasensitivity and noise propagation in a synthetic transcriptional cascade. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Kang Wu,et al.  A modular positive feedback-based gene amplifier , 2010, Journal of biological engineering.

[27]  Sudeshna Sinha,et al.  Reliable logic circuit elements that exploit nonlinearity in the presence of a noise floor. , 2009, Physical review letters.

[28]  G. Balázsi,et al.  Negative autoregulation linearizes the dose–response and suppresses the heterogeneity of gene expression , 2009, Proceedings of the National Academy of Sciences.

[29]  A. Jeffrey,et al.  How the λ repressor and cro work , 1980, Cell.

[30]  R. Sauer,et al.  [76] Bacteriophage λ repressor and cro protein: Interactions with operator DNA , 1980 .

[31]  Sudeshna Sinha,et al.  A noise-assisted reprogrammable nanomechanical logic gate. , 2010, Nano letters.

[32]  Shankar Mukherji,et al.  Synthetic biology: understanding biological design from synthetic circuits , 2009, Nature Reviews Genetics.

[33]  M. Thattai,et al.  Intrinsic noise in gene regulatory networks , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  B. Séraphin,et al.  Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion , 2001, The EMBO journal.

[35]  J. Collins,et al.  Tuning and controlling gene expression noise in synthetic gene networks , 2010, Nucleic acids research.

[36]  David K. Karig,et al.  Signal-amplifying genetic circuit enables in vivo observation of weak promoter activation in the Rhl quorum sensing system. , 2005, Biotechnology and bioengineering.

[37]  Jeff Hasty,et al.  Designer gene networks: Towards fundamental cellular control. , 2001, Chaos.

[38]  N. Goel,et al.  Stochastic models in biology , 1975 .

[39]  G. K. Ackers,et al.  Quantitative model for gene regulation by lambda phage repressor. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[40]  H. Risken Fokker-Planck Equation , 1984 .

[41]  L. Serrano,et al.  Engineering stability in gene networks by autoregulation , 2000, Nature.

[42]  M. Elowitz,et al.  Functional roles for noise in genetic circuits , 2010, Nature.

[43]  H. McAdams,et al.  Circuit simulation of genetic networks. , 1995, Science.

[44]  C. Rao,et al.  Control, exploitation and tolerance of intracellular noise , 2002, Nature.

[45]  A. Arkin,et al.  Stochastic mechanisms in gene expression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Martin Fussenegger,et al.  A genetic time‐delay circuitry in mammalian cells , 2007, Biotechnology and bioengineering.

[47]  Kurt Wiesenfeld,et al.  Stochastic resonance and the benefits of noise: from ice ages to crayfish and SQUIDs , 1995, Nature.

[48]  Sonja J. Prohaska,et al.  “Genes” , 2008, Theory in Biosciences.

[49]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[50]  Jeff Hasty,et al.  Engineered gene circuits , 2002, Nature.

[51]  M Ptashne,et al.  Gene regulation at the right operator (OR) of bacteriophage lambda. II. OR1, OR2, and OR3: their roles in mediating the effects of repressor and cro. , 1980, Journal of molecular biology.