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SynBio3D: Establishing the engineering fundamentals of three-dimensional synthetic biology

SynBio3D：建立三维合成生物学的工程基础

基本信息

批准号：
EP/R019002/1
负责人：
Angel Goni-Moreno
金额：
$ 12.88万
依托单位：
Newcastle University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FR019002%2F1
关键词：
SynBio3D Establishing engineering fundamentals three

项目摘要

Synthetic biology applies rational engineering principles to the design and build of novel biomolecular devices. This allows us to use synthetic genetic 'circuits' to program microbes to behave as living processing units. A fundamental aim is to obtain useful (human-defined) behaviour in living systems. This approach builds on the predictive power of mathematical modelling and the current understanding of molecular biology to engineer organisms that will ultimately be of major value to society. Applications of these programmed microbes include biotechnological processes, from the production of biofuels to pharmaceuticals, bioremediation strategies, agriculture and bio-diagnostics. However, there is currently one issue which threatens to undermine the success of synthetic biology going forwards: the complete disregard for spatial dimensions. This is in contrast to many other engineering disciplines, where the design of a complex system such an airplane must specify accurate physical locations for its circuit's components. To date, synthetic biology has no spatial resolution apart from the notions of inside and outside the cell. Novel biological genetic circuits are introduced inside cells with no notable attention to their whereabouts.A major problem with this is that a cell is abstracted as a black box, thus viewed in terms of inputs/outputs alone without considering its internal workings. The exclusion of such information causes important problems when the organisms come to be used/tested. It is commonly required to re-engineer and retest the circuit with different genetic parts to fine-tune its function. That "refactoring" process is not only time consuming and costly but also unnecessary in many cases - if spatial dimensions were considered at the design stage. For example, our initial investigations have recently shown that the physical distance between the components of a given genetic circuit can change its functioning considerably. Therefore, the awareness of geometrical effects will assist the design of robust and predictable circuits. Each gene sequence and each protein may need a specific physical address in the spatial frame of a cell for optimal performance, a question that urgently needs further attention to enable synthetic biology to fulfil its potential. In this first grant, we will measure the impact of space in synthetic constructs and use it to establish the fundamentals of a new concept that we refer to as 'three-dimensional synthetic biology'.SynBio3D will upgrade the synthetic biology lifecycle by adding spatial information, a goal unattained by any other research group to date. The project will address two major barriers to achieve success. Firstly, mathematical models, which are at the heart of genetic circuit development, are overwhelmingly based on time as the only reference. This restricts the way we represent biomolecular interactions to time-based kinetics, which assume an unrealistic zero-dimensional scenario. In response to this first problem we will develop novel computational methods to allow us to simulate genetic circuits using spatial constraints such as distances and molecular crowding. The second problem concerns the direct visualization in vivo of gene locations and single-molecule displacements. We will use super-resolution microscopy to obtain three-dimensional, real-time measurements of bespoke genetic circuits. Together, the resulting information will formally correlate, for the first time, a genetic circuit's dynamics in time with its geometrical features in space. This will allow to formalize spatial engineering fundamentals.This three-dimensional approach to synthetic biology will lead the way in turning molecular networks into programmable systems; a goal revealed to be elusive with traditional time-based approaches. Furthermore, it will impact research lines in apparently distant fields ranging from biophysics to computer science.

合成生物学应用合理的工程原理来设计和建造新的生物分子装置。这使我们能够使用合成的基因“电路”来编程微生物，使其作为活的处理单元。一个基本目标是获得生命系统中有用的（人类定义的）行为。这种方法建立在数学建模的预测能力和当前对分子生物学的理解之上，以设计最终对社会具有重大价值的生物体。这些编程微生物的应用包括生物技术过程，从生产生物燃料到制药、生物修复策略、农业和生物诊断。然而，目前有一个问题威胁着合成生物学未来的成功：对空间维度的完全忽视。这与许多其他工程学科形成对比，在这些学科中，像飞机这样的复杂系统的设计必须为其电路组件指定准确的物理位置。迄今为止，除了细胞内外的概念外，合成生物学还没有空间分辨率。新的生物遗传电路被引入细胞内，没有注意到它们的位置。这样做的一个主要问题是，单元被抽象为一个黑盒，因此仅从输入/输出的角度来看待，而不考虑其内部工作原理。排除这些信息会在使用/测试生物体时造成重大问题。通常需要用不同的基因部分重新设计和重新测试电路，以微调其功能。这种“重构”过程不仅耗时耗钱，而且在很多情况下是不必要的——如果在设计阶段就考虑到空间维度的话。例如，我们的初步调查最近表明，一个给定遗传回路的组成部分之间的物理距离可以在很大程度上改变其功能。因此，几何效应的意识将有助于稳健和可预测电路的设计。每个基因序列和每个蛋白质可能需要在细胞的空间框架中有一个特定的物理地址以获得最佳性能，这是一个迫切需要进一步关注的问题，以使合成生物学能够发挥其潜力。在第一笔拨款中，我们将测量空间对合成结构的影响，并利用它来建立一个新概念的基础，我们称之为“三维合成生物学”。SynBio3D将通过添加空间信息来升级合成生物学的生命周期，这是迄今为止任何其他研究小组都没有达到的目标。该项目将解决取得成功的两个主要障碍。首先，作为遗传回路发展核心的数学模型，绝大多数是基于时间作为唯一参考。这限制了我们将生物分子相互作用表示为基于时间的动力学的方式，这假设了一个不切实际的零维场景。为了解决这第一个问题，我们将开发新的计算方法，使我们能够利用距离和分子拥挤等空间限制来模拟遗传电路。第二个问题涉及体内基因位置和单分子位移的直接可视化。我们将使用超分辨率显微镜获得定制基因电路的三维实时测量。总之，所得到的信息将首次正式地将遗传电路在时间上的动态与其在空间上的几何特征联系起来。这将使空间工程的基本原理形式化。这种合成生物学的三维方法将引领将分子网络转变为可编程系统的道路；传统的基于时间的方法难以实现这一目标。此外，它将影响从生物物理学到计算机科学等看似遥远的领域的研究方向。

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）

Dynamical Task Switching in Cellular Computers

DOI：
10.3390/life9010014
发表时间：
2019-01-26
期刊：
LIFE-BASEL
影响因子：
3.2
作者：
Goni-Moreno, Angel;de la Cruz, Fernando;Amos, Martyn
通讯作者：
Amos, Martyn

Communicating Structure and Function in Synthetic Biology Diagrams.

DOI：
10.1021/acssynbio.9b00139
发表时间：
2019-08-16
期刊：
ACS synthetic biology
影响因子：
4.7
作者：
Beal J;Nguyen T;Gorochowski TE;Goñi-Moreno A;Scott-Brown J;McLaughlin JA;Madsen C;Aleritsch B;Bartley B;Bhakta S;Bissell M;Castillo Hair S;Clancy K;Luna A;Le Novère N;Palchick Z;Pocock M;Sauro H;Sexton JT;Tabor JJ;Voigt CA;Zundel Z;Myers C;Wipat A
通讯作者：
Wipat A

The Synthetic Biology Open Language (SBOL) Version 3: Simplified Data Exchange for Bioengineering.

DOI：
10.3389/fbioe.2020.01009
发表时间：
2020
期刊：
Frontiers in bioengineering and biotechnology
影响因子：
5.7
作者：
McLaughlin JA;Beal J;Mısırlı G;Grünberg R;Bartley BA;Scott-Brown J;Vaidyanathan P;Fontanarrosa P;Oberortner E;Wipat A;Gorochowski TE;Myers CJ
通讯作者：
Myers CJ

Capturing Multicellular System Designs Using Synthetic Biology Open Language (SBOL).

使用合成生物学开放语言 (SBOL) 捕获多细胞系统设计。