Adventurous Manufacturing Follow On: Integrating Living Analytics into Biomanufacturing Processes

冒险制造的后续:将实时分析集成到生物制造流程中

基本信息

  • 批准号:
    EP/W00979X/1
  • 负责人:
  • 金额:
    $ 110.91万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

Cells possess a variety of mechanisms to sense their environment and adapt to changes by changing the proteins they express. Using synthetic biology methods, it is possible to co-opt these methods to develop analytical tools to report the concentrations of key metabolites of interest for researchers in biomanufacturing. We call these analytical tools whole-cell biosensors. However, developing the whole-cell biosensor is only one part of the challenge. In order to be able to use these in biomanufacturing, we need a way to limit the growth of the whole-cell biosensor and prevent them from having negative interactions with the other cells in the manufacturing process. In a proof-of-concept grant from Round 1, we showed that encapsulation of the whole-cell biosensor in polymeric spheres made of multiple layers allowed them to retain their biosensing capability and be grown together with mammalian cells making a protein product without negatively affecting the behaviour of the mammalian cells. In this research, we aim to expand on these findings and, together with our industrial partners, demonstrate the potential of this concept in industrial biomanufacturing.Part 1 of the proposed research will make adjustments to our initial proof-of-concept to make it more compatible with industrial use. This will involve making some changes to the biosensor circuit to make the output easier to interpret and to see changes that occur in a faster time frame. It will also involve making our polymer spheres smaller so that they are more compatible with instruments used to measure fluorescence. Finally, we will show that the biosensor can be used in a bioreactor where it is grown alongside mammalian cells expressing a protein.Part 2 of the proposed research will develop a concept where the biosensor does not just report the concentration of the analyte, but goes beyond this to adjust the concentration via the expression of enzymes. This will combine two steps in the control of manufacturing processes-sensing and actuation-into the biosensor. To do this, we will modify our original design so that the cells express enzymes that can metabolise the analyte when it is detected. We will also test whether different types of polymer and different shapes (other than spheres) work better in this application. Finally, we will try the system in a bioreactor and test how much metabolite the biosensor can degrade per unit area of the polymer. This will inform the feasibility of using this at larger scales.Part 3 of the proposed research will build on the work so far to exchange the type of organism used as the host for the biosensor and show that the concept can work for other analytes beyond our initial example. Here we will explore organisms used in food processing as well as natural bacteria that live with and are not harmful for human hosts. The additional analytes that will be explored have been chosen to represent a wide range of chemical structures in order to assess if there are any restrictions on the kind of molecules we can detect.By the end of the project, we will have developed our initial concept further and facilitated its translation into industry. We have successfully demonstrated a new concept in analytical technology that we think can have a lasting impact on how biomanufacturing processes are analysed and controlled.
细胞具有多种机制来感知它们的环境,并通过改变它们表达的蛋白质来适应变化。使用合成生物学方法,可以选择这些方法来开发分析工具,以报告生物制造研究人员感兴趣的关键代谢物的浓度。我们称这些分析工具为全细胞生物传感器。然而,开发全细胞生物传感器只是挑战的一部分。为了能够在生物制造中使用它们,我们需要一种方法来限制全细胞生物传感器的生长,并防止它们在制造过程中与其他细胞发生负面相互作用。在第一轮的概念验证资助中,我们表明,将全细胞生物传感器封装在由多层制成的聚合物球体中,使它们能够保持其生物传感能力,并与哺乳动物细胞一起生长,从而产生蛋白质产物,而不会对哺乳动物细胞的行为产生负面影响。在这项研究中,我们的目标是扩大这些发现,并与我们的工业合作伙伴一起,证明这一概念在工业生物制造中的潜力。拟议研究的第1部分将对我们最初的概念验证进行调整,使其更适合工业用途。这将涉及对生物传感器电路进行一些更改,以使输出更容易解释并查看在更快的时间范围内发生的变化。它还将涉及使我们的聚合物球体更小,以便它们与用于测量荧光的仪器更兼容。最后,我们将展示生物传感器可以用于生物反应器,在那里它与表达蛋白质的哺乳动物细胞一起生长。拟议研究的第2部分将开发一个概念,其中生物传感器不仅报告分析物的浓度,而且还通过酶的表达来调节浓度。这将联合收割机的两个步骤,在控制制造过程中的传感和驱动到生物传感器。为了做到这一点,我们将修改我们的原始设计,使细胞表达酶,可以代谢分析物时,它被检测到。我们还将测试不同类型的聚合物和不同形状(除了球体)是否在此应用中更好地工作。最后,我们将在生物反应器中尝试该系统,并测试生物传感器每单位面积的聚合物可以降解多少代谢物。这将告知在更大规模上使用它的可行性。拟议研究的第3部分将建立在迄今为止的工作基础上,以交换用作生物传感器宿主的生物体类型,并表明该概念可以适用于我们最初示例之外的其他分析物。在这里,我们将探索用于食品加工的生物以及与人类宿主一起生活且对人类宿主无害的天然细菌。为了评估我们能够检测的分子种类是否存在任何限制,我们选择了代表广泛化学结构的额外分析物。在项目结束时,我们将进一步发展我们的初始概念,并促进其转化为工业。我们已经成功地展示了分析技术中的一个新概念,我们认为它可以对生物制造过程的分析和控制产生持久的影响。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Encapsulation of bacteria in bilayer Pluronic thin film hydrogels: a safe format for engineered living materials
将细菌封装在双层 Pluronic 薄膜水凝胶中:工程活性材料的安全形式
  • DOI:
    10.1101/2022.09.29.510162
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bhusari S
  • 通讯作者:
    Bhusari S
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Karen Polizzi其他文献

The sound of silence: Transgene silencing in mammalian cell engineering
沉默的声音:哺乳动物细胞工程中的转基因沉默
  • DOI:
    10.1016/j.cels.2022.11.005
  • 发表时间:
    2022-12-21
  • 期刊:
  • 影响因子:
    7.700
  • 作者:
    Alan Cabrera;Hailey I. Edelstein;Fokion Glykofrydis;Kasey S. Love;Sebastian Palacios;Josh Tycko;Meng Zhang;Sarah Lensch;Cara E. Shields;Mark Livingston;Ron Weiss;Huimin Zhao;Karmella A. Haynes;Leonardo Morsut;Yvonne Y. Chen;Ahmad S. Khalil;Wilson W. Wong;James J. Collins;Susan J. Rosser;Karen Polizzi;Tara L. Deans
  • 通讯作者:
    Tara L. Deans

Karen Polizzi的其他文献

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{{ truncateString('Karen Polizzi', 18)}}的其他基金

Cell-free synthetic biology for combinatorial biosensor design (SYNSENSO)
用于组合生物传感器设计的无细胞合成生物学 (SYNSENSO)
  • 批准号:
    EP/X030792/1
  • 财政年份:
    2022
  • 资助金额:
    $ 110.91万
  • 项目类别:
    Research Grant
Developing a rapid quality control and long-term stability assay for RNA vaccine candidates
开发 RNA 候选疫苗的快速质量控制和长期稳定性测定方法
  • 批准号:
    BB/W010771/1
  • 财政年份:
    2021
  • 资助金额:
    $ 110.91万
  • 项目类别:
    Research Grant
Understanding and manipulating lactate metabolism in single cells
了解和操纵单细胞中的乳酸代谢
  • 批准号:
    BB/S006206/1
  • 财政年份:
    2019
  • 资助金额:
    $ 110.91万
  • 项目类别:
    Research Grant
Integrating living analytics into biomanufacturing processes
将生活分析集成到生物制造流程中
  • 批准号:
    EP/T005297/1
  • 财政年份:
    2019
  • 资助金额:
    $ 110.91万
  • 项目类别:
    Research Grant
A platform for the optimisation of metabolic pathways for glycosylation to achieve a narrow and targeted glycoform distribution
用于优化糖基化代谢途径以实现狭窄且有针对性的糖型分布的平台
  • 批准号:
    BB/I017011/1
  • 财政年份:
    2011
  • 资助金额:
    $ 110.91万
  • 项目类别:
    Research Grant

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