Transforming cells into automataI From biology to automataGoalHow can we use this?II BackgroundThe central dogma of biology.III Digital componentsThe AND gate produces a high signal on the output (1) only when both of its inputs are also high. Biologically, we can represent this by a taking a not-AND gate, a NAND gate, and flipping its result. In the diagram below, X and Y are repressors on two copies of gene producing another repressor. When X and Y are present, none of the repressor exists and the final product, Z, can be produced.Completion of propositional logic under NAND operatorTransforming cells into automata CS374 Fall 2004, Lecture 5,10/12/04Lecturer: Florian Buron Scribe: Vincent DorieTransforming cells into automataBased on the following papers: 1. Weiss R, Basu S, Hooshangi S, Kalmbach A, Karig D, Mehreja R, Netravali I. “Genetic CircuitBuilding Blocks for Cellular Computation, Communications, and Signal Processing”, NaturalComputing, an International Journal, 47-84, (2) 2003.2. Gardner TS, Cantor CR, Collins JJ. “Construction of a genetic toggle switch in Escherichiacoli”, Nature, 339-342 Vol. 403, 20 Jan. 2000.I From biology to automataGoalComputers are deterministic computing devices whereas cells are stochastic andgenerally hard to control. The primary goal of the works is to take the randomnature of the cell and use its machinery in a deterministic fashion by introducingelements that can be closely regulated. The cell has natural mechanisms forcontrol that can be exploited. The algorithm we are looking at is to modifyProtein -> DNA -> Proteinpathways such that the input determines the output.How can we use this?- Drug and biomaterial production and creation. To a large part this isalready done by introducing desired genes into a replicating hostpopulation which then produces the materials for harvest.- Programmed therapeutics. The concept is to be able to have cells in thebody which only release their drug when signaled, or after a period ofrecovery.- Embedded intelligence in materials. Quite a bit more far fetched, this isequivalent to a network of sensors which can themselves permeate amaterial and maintain communication. Currently the ability to do this ismany years in the future.- Environmental sensing and effecting. Similar to programmed therapeuticsand embedded intelligence.- Nanoscale fabrication. This is an exciting topic but relies on ourunderstanding of protein interactions and folding.II BackgroundThe central dogma of biology.DNA -> RNA -> proteinTransforming cells into automata CS374 Fall 2004, Lecture 5,10/12/04Lecturer: Florian Buron Scribe: Vincent DorieEverywhere in this chain of interactions lies the possibility for regulatorymechanisms. The simplest is at the start, by controlling what RNA is produced byRNA polymerase. RNA transcription commences at promoter regions of DNA,therefore by introducing a promoter we can control what downstream of itbecomes a protein.Regulatory pathways.It is important to understand our toolset. Repressor proteins can bind to the DNAnear the promoter to prevent transcription by masking the signal. Activatorproteins can help attract RNA polymerase to the promoter region. More complexinteractions exist, and many of these proteins have cofactors that modify theirbehavior. For instance, we can turn a repressor off (enabling transcription) byattaching a phosphate to it which changes it conformation.The essential thing to remember about biology is that it is sloppy. All reactionshappen to varying degrees. Even in the presence of a good repressor, somemRNA may leak and the protein produced in small levels. Other types of controlcan also exist, for example where mRNA is being produced but then destroyedby another reaction before protein is synthesized. Additionally, signals are notnecessarily transient. Proteins and mRNA take time to decay and this affects thespeed of the reaction. This is a complicated domain which requires very goodcontrols in the experimental design.III Digital components Digital basics.Digital electronics function in a language of {0, 1}, with 0 usually being 0 voltsand 1 being 5 volts. To incorporate some noise, a bit of slop is given between 0and 1 where a threshold exists. Digital devices need to behave deterministically,therefore the values 0 and 1 and well defined. These devices take a series ofinputs and perform some operation on them, which becomes part of the output.The output themselves requires some discussion. In digital components, signalstransfer down wires. Theoretically, in cellular components, signals propagatethrough space. Without cellular targeting, to avoid unintentional signaling, theoutput must have a different conformation that the inputs. Feedback loops arepossible, but we would only want that where the circuit design demands it.Therefore, a different pathway is required for most every computation we wish torun.Transforming cells into automata CS374 Fall 2004, Lecture 5,10/12/04Lecturer: Florian Buron Scribe: Vincent DorieDigital inverter.The inverter is the simplest component and flips whatever signal it is given. If 0 isits input, 1 is the output. This is signified by the symbols at the top of thefollowing diagram. We can replicate this simple component in vivo by a singlerepressor system. In the absence of the repressor, a different protein isreproduced. When the repressor is present, the gene is not transcribed and noproduct is produced.Side note: repressor design.This system can be improved by using a strong repressor molecule. In theexperimental design of Weiss, et al., they used a repressor that forms a dimer.This mimics a threshold function, whereby when a small amount of repressor isavailable it lacks the kinetics to dimerize. After enough has been produced toform sufficient dimers, they bond tightly to the DNA and prevent transcription. Inmonomer design, there would be low levels of repression continually, up until thepoint where enough repressor had been produced. Therefore, the product wouldlinearly follow the repressor.AND gate.Transforming cells into automata CS374 Fall 2004, Lecture 5,10/12/04Lecturer: Florian Buron Scribe: Vincent DorieThe AND gate produces a high signal on the
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