In vivo integral feedback control for robust synthetic biology

用于稳健合成生物学的体内积分反馈控制

基本信息

  • 批准号:
    EP/K020617/1
  • 负责人:
  • 金额:
    $ 47.6万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2013
  • 资助国家:
    英国
  • 起止时间:
    2013 至 无数据
  • 项目状态:
    已结题

项目摘要

Biotechnology companies use single cells (bacteria, yeast, or mammalian) as 'cell factories' to produce molecules of use in many different sectors, such as pharmaceuticals, enzymes, biofuels, cosmetics or fragrances. In some cases this means that compounds that were previously produced from non-renewable sources (petroleum) can be produced from renewable sources. In other cases cell factories produce useful compounds that would be impossible, too difficult, or too expensive to produce in other ways (e.g. using chemistry). To date, innovation for biotechnological processes has focused on maximising output, but now the challenge is to use cell factories more efficiently by reducing the required input of energy and nutrients. Moreover, as we learn more about how to design and control living cells, we can begin to envision new exciting potential uses for these 'living machines', especially in the healthcare sector.In order to do this, we need to be able to engineer living cells that behave controllably in the face of changing conditions. This is what this project aims to achieve. In electronic, mechanical and chemical engineering, robust control is typically accomplished through the use of 'Integral Feedback Control', which is an effective strategy to guarantee robustness to step-like perturbations and uncertainties. This requires an integrator. In a nutshell, the integrator accumulates information about the system's past behaviour and uses it to adjust and improve its activity as more information becomes available. Integral Feedback Control allows, for example, cruise control systems to maintain a car at constant speed irrespective of the slope of the road or the combined weight of the passengers; or the speed of an escalator to remain constant regardless of the number of people using it. In this project, we will design, model, construct and test a biological integrator to implement 'in-vivo robust control'.A fully (re-)programmable and controllable cell is one of the core long-term objectives of the blossoming field of synthetic biology. However, no biological integrator currently exists. To fill this gap, we will engineer the first in vivo 'plug-and-play' bio-integrator device that can be customised for different applications. To demonstrate the functionality of our bio-integrator device, we will use it to create engineered cells that can robustly maintain the concentration of a chosen small molecule around a specified value. To accomplish this, the cell will be equipped with both the ability to sense the extracellular concentration of the molecule and to synthesise and secrete the molecule itself. A rigorous control design will allow for the secretion rate to change dynamically so as to counteract step-like perturbations in the extracellular concentration of the molecule. This will establish the necessary theoretical and experimental basis for future extension of this research into in vivo environments.For example, a biological integrator device would make it possible to engineer microbes that reside symbiotically with or within other organisms, and that are able to sense and self-adjust to changing and uncertain external conditions. We anticipate that this in turn could lead to the emergence of a revolutionary new form of medicine that we are calling 'active in vivo medicine', i.e. cells that are implanted in patients and monitor the concentration of disease-related biomolecules (e.g. insulin), modulating their production of these molecules in response to patient need.In order to investigate how active in vivo medicine might be implemented in real-world conditions, we have integrated into this project a programme of work on 'Responsible Research and Innovation' designed to incorporate the perspectives of a wide range of interested parties into any future development of active in vivo medicine, including: biomedical researchers, clinicians, patient groups, regulators, pharmaceutical firms, and bioethicists.
生物技术公司使用单细胞(细菌、酵母或哺乳动物)作为“细胞工厂”,生产用于许多不同领域的分子,如制药、酶、生物燃料、化妆品或香水。在某些情况下,这意味着以前由不可再生资源(石油)生产的化合物可以由可再生资源生产。在其他情况下,细胞工厂生产有用的化合物,这是不可能的,太困难,或太昂贵,以其他方式生产(例如使用化学)。迄今为止,生物技术过程的创新一直集中在最大限度地提高产量,但现在的挑战是通过减少所需的能量和营养物质的投入来更有效地利用细胞工厂。此外,随着我们对如何设计和控制活细胞的了解越来越多,我们可以开始设想这些“活机器”的新的令人兴奋的潜在用途,特别是在医疗保健领域。为了做到这一点,我们需要能够设计出在不断变化的条件下行为可控的活细胞。这就是该项目的目标。在电子、机械和化学工程中,鲁棒控制通常通过使用“积分反馈控制”来实现,这是一种保证对阶跃扰动和不确定性具有鲁棒性的有效策略。这就需要一个积分器。简而言之,集成器积累有关系统过去行为的信息,并在更多信息可用时使用它来调整和改进其活动。积分反馈控制允许,例如,巡航控制系统,以保持汽车在恒定的速度,而不管道路的坡度或乘客的组合重量;或自动扶梯的速度保持不变,而不管使用它的人数。在这个项目中,我们将设计,建模,构建和测试生物集成器以实现“体内鲁棒控制”。完全(可重新)可编程和可控的细胞是合成生物学蓬勃发展领域的核心长期目标之一。然而,目前不存在生物整合剂。为了填补这一空白,我们将设计第一个体内“即插即用”的生物集成设备,可以针对不同的应用进行定制。为了证明我们的生物整合器设备的功能,我们将使用它来创建工程细胞,这些细胞可以将选定的小分子的浓度稳定地保持在指定值附近。为了实现这一点,细胞将配备有感知分子的细胞外浓度以及合成和分泌分子本身的能力。严格的控制设计将允许分泌速率动态变化,以抵消分子的细胞外浓度的阶梯状扰动。这将为将来将这项研究扩展到体内环境建立必要的理论和实验基础。例如,生物集成装置将使工程化的微生物与其他生物体共生,并且能够感知和自我调节以适应变化和不确定的外部条件。我们预计,这反过来可能导致出现一种革命性的新形式的药物,我们称之为“活性体内药物”,即植入患者体内并监测疾病相关生物分子浓度的细胞(例如胰岛素),为了研究如何在体内活性药物可以在真实的-在当今世界的条件下,我们将“负责任的研究和创新”的工作计划纳入了该项目,旨在将广泛的利益相关方的观点纳入活性体内医学的任何未来发展,包括:生物医学研究人员,临床医生,患者团体,监管机构,制药公司和生物伦理学家。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Tuning the dials of Synthetic Biology.
  • DOI:
    10.1099/mic.0.067975-0
  • 发表时间:
    2013-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Arpino JAJ;Hancock EJ;Anderson J;Barahona M;Stan GV;Papachristodoulou A;Polizzi K
  • 通讯作者:
    Polizzi K
Investigating the consequences of asymmetric endoplasmic reticulum inheritance in Saccharomyces cerevisiae under stress using a combination of single cell measurements and mathematical modelling.
  • DOI:
    10.1016/j.synbio.2018.01.001
  • 发表时间:
    2018-03
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Jonas FRH;Royle KE;Aw R;Stan GV;Polizzi KM
  • 通讯作者:
    Polizzi KM
Simplified mechanistic models of gene regulation for analysis and design.
  • DOI:
    10.1098/rsif.2015.0312
  • 发表时间:
    2015-07-06
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hancock EJ;Stan GB;Arpino JA;Papachristodoulou A
  • 通讯作者:
    Papachristodoulou A
A Systems Theoretic Approach to Systems and Synthetic Biology I: Models and System Characterizations
系统和合成生物学的系统理论方法 I:模型和系统表征
  • DOI:
    10.1007/978-94-017-9041-3_7
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kuntz J
  • 通讯作者:
    Kuntz J
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Guy-Bart Stan其他文献

Global analysis of limit cycles in networks of oscillators
  • DOI:
    10.1016/s1474-6670(17)31382-4
  • 发表时间:
    2004-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Guy-Bart Stan;Rodolphe Sepulchre
  • 通讯作者:
    Rodolphe Sepulchre

Guy-Bart Stan的其他文献

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{{ truncateString('Guy-Bart Stan', 18)}}的其他基金

A novel, fast and efficient resource recycling system for improving the performance of engineered bacteria
一种新颖、快速、高效的资源回收系统,用于提高工程细菌的性能
  • 批准号:
    EP/P009352/1
  • 财政年份:
    2017
  • 资助金额:
    $ 47.6万
  • 项目类别:
    Research Grant
Genetically Encoded Nucleic Acid Control Architectures
基因编码核酸控制架构
  • 批准号:
    EP/P02596X/1
  • 财政年份:
    2017
  • 资助金额:
    $ 47.6万
  • 项目类别:
    Research Grant
Engineering Fellowships for Growth: Systems and control engineering framework for robust and efficient synthetic biology
增长工程奖学金:用于稳健和高效合成生物学的系统和控制工程框架
  • 批准号:
    EP/M002187/1
  • 财政年份:
    2015
  • 资助金额:
    $ 47.6万
  • 项目类别:
    Fellowship
Data-based optimal control of synthetic biology gene circuits
基于数据的合成生物学基因电路优化控制
  • 批准号:
    EP/J014214/1
  • 财政年份:
    2012
  • 资助金额:
    $ 47.6万
  • 项目类别:
    Research Grant

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