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University of Birmingham the Chaos Within University of Birmingham The chaos within Johnston, Iain G. DOI: 10.1111/j.1740-9713.2012.00586.x License: None: All rights reserved Document Version Peer reviewed version Citation for published version (Harvard): Johnston, IG 2012, 'The chaos within: exploring noise in cellular biology', Significance: statistics making sense, vol. 9, no. 4, pp. 17-21. https://doi.org/10.1111/j.1740-9713.2012.00586.x Link to publication on Research at Birmingham portal Publisher Rights Statement: This is the peer reviewed version of the following article: Johnston, I. (2012), The chaos within: Exploring noise in cellular biology. Significance, 9: 17–21. , which has been published in final form at http://dx.doi.org/10.1111/j.1740-9713.2012.00586.x. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. •User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?) •Users may not further distribute the material nor use it for the purposes of commercial gain. Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive. If you believe that this is the case for this document, please contact [email protected] providing details and we will remove access to the work immediately and investigate. Download date: 28. Sep. 2021 The chaos within: exploring noise in cellular biology Iain G. Johnston Systems & Signals Group, University of Oxford, Clarendon Laboratory, Parks Road, Oxford, UK I say unto you: a man must have chaos yet within factories, which would read them and produce these essen- him to be able to give birth to a dancing star. I tial machines as needed, enabling the city to function. In say unto you: ye have chaos yet within you... this metaphor the central library is our DNA, power sta- Nietzsche, Thus Spake Zarathustra tions are our mitochondria, and factories our ribosomes. The machines, as we have said, are proteins, the library's books are genes (each containing the instructions on how to build a protein) and the copies of those books are mRNA A brewery in a bouncy castle molecules, which convey this information and are `trans- lated' to produce proteins. This process, illustrated in Fig Cellular biology exists embedded in a world dominated 2a, is often referred to as the central dogma of cellular biol- by random dynamics and chance. Many vital molecules ogy: genes are first transcribed to mRNA, then translated and pieces of cellular machinery diffuse within cells, mov- to form proteins, the building blocks of the cell. ing along random trajectories as they collide with the other However, our cities are very unpredictable places. First biomolecular inhabitants of the cell. Cellular components of all, things fall apart rather quickly. The copies of build- may block each other's progress, be produced or degraded ing instructions { the mRNAs { are particularly prone to at random times, and become unevenly separated as cells this. Worse, the library only makes some of its books acces- grow and divide. Cellular behaviour, including important sible at a time. The unpredictable opening and closing of features of stem cells, tumours and infectious bacteria, is books, and random nature of production and degradation profoundly influenced by the chaos which is the environ- in our metaphorical cities, are inevitable consequences of ment within the cell walls. the random dynamics in cells: in biology, these processes all How can the delicate processes that give rise to life take involve chance collisions and rearrangements of molecules place in this random world? And what can statistics tell within the chaotic interiors of cells. So, if we happen to us about the probability of things going wrong? The study find a book open and make a copy of its contents, we can of cellular noise { the causes and effects of randomness make several of the corresponding protein machines { but within cellular biology { is a rapidly growing area within the book may close and the copies may degrade very soon, biostatistics attempting to describe these phenomena. and we are stuck with this small number. (This is the copy Modern statistical methods and the explosion of recent number of the protein, and it can range between dozens in a results from experimental biology are allowing us to un- cell and thousands.) Our city may require a particular ma- derstand this essential randomness of cellular systems in chine { a particular protein { with some urgency, but if the hitherto unrivalled detail. Here we will look at some im- corresponding book only opens rarely and the instruction portant causes and effects of randomness in cellular biol- copies degrade quickly, we may be unable to produce that ogy, and some ways in which researchers, helped by the protein in sufficient numbers to function. If books open vast amounts of data that are now flowing in, have made and close several times, we will see unpredictable `bursts' progress in describing the randomness of nature. of production in the cell. The copy number of a cellular machine, dependent on these random processes, is there- fore uncertain, giving rise to a spread of possible values at Cities built on shaky ground any time, and leading to variability in a city's ability to arXiv:1208.2250v1 [q-bio.CB] 10 Aug 2012 perform biological tasks. The inner workings of a cell can roughly be pictured as an industrial city, with many different processes contributing to the city's well-being. Among these are `power stations' Genes rolling dice which produce fuel that other industries harness, a central library where the blueprints for useful machinery are stored, Much of the existing work on cellular noise has consid- and factories which produce these machines. Cellular ma- ered variability in gene expression { the levels at which the chines { we call them proteins { perform many of the tasks products of genes are present within cells. Most of the cells we view as essential to life: the digestion of food (machines in our bodies are genetically identical: for example, muscle chemically break down nutrients); movement (machines in cells are genetically identical to brain cells. But the two muscle fibres exert forces on each other to move that fibre); are very different in appearance, behaviour and biochemi- production of energy (machines that create chemical fuels) cal profile. A fundamental reason for this is the differences and so on. In an ideal world, the city would produce copies in gene expression within different cells: although cells may of the information in the library and distribute them to contain the same genetic information, only a subset of genes 2 A. Gene expression produces proteins from DNA instructions. mRNA Protein TF RNA Pol Transcription Translation Activated, transcribing DNA DNA Activation Degradation Ø Ø Inactive DNA B. Intrinsic and extrinsic noise: dual reporter studies. FIG. 1: Picturing noise in cellular biology. Left: Measurements of the mitochondrial content of cells (yellow is high mitochondrial density, purple is low) showing significant variability in the number of `power stations' between otherwise similar cells. Right: Green Green speckles are sites where transcription is taking place (the first stage Intrinsic of gene expression). Some cells { like the large yellow one { transcribe quickly, producing more cellular machinery, whereas some { like the Extrinsic redder ones { show very little transcriptional activity. Images from Ref. [1]. Yellow are expressed { `turned on' { in any given cell, and the ones that are turned on determine what the cell is and what it FIG. 2: Noise in gene expression. A. The `central dogma' of does. The genes expressed in a cell are an important de- cell biology, whereby DNA is activated and transcribed to produce termining factor of its `cell type' (including its appearance, mRNA, which is translated to produce proteins. In the metaphor behaviour, and other attributes), allowing different cells to in the main text, this process is represented by the opening of li- fulfill different roles in our bodies. To express this in terms brary books which are interpreted to produce blueprints, which are distributed and assembled to produce machinery. B. Quantifying in- of our metaphor, some city libraries may intentionally keep trinsic and extrinsic noise in a population of cells. In the graph the books on particular machines open more than others, so long diagonal line shows variations in overall brightness, due to ex- that, for example, one cell-city produces lots of proteins trinsic noise; cells near its origin have few fluorescing genes, those that process raw materials, and another produces proteins near the end have many. The shorter arrows show cells glowing more that facilitate movement. green or more yellow; their variation is not in number of genes, but in the proportion of green and yellow ones.
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