Fast DNA Sequencing Using Near-field Microwave Sensors

使用近场微波传感器进行快速 DNA 测序

• 批准号: BB/X003256/1
• 负责人: Antonio Lombardo
• 金额: $ 23.09万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX003256%2F1
• 关键词: Fast; DNA; Sequencing; Using; Near

DNA is the nucleic acid that passes information from parent to child in living systems. Determining the order of the four information-carrying bases, (denoted A,C,G,T) is known as "sequencing". Such sequencing is at the core of modern molecular biology and genetic epidemiology and has huge potential for applications in diagnosis and precision medicine. Since the pioneering work that led to the first sequencing of the human genome about 20 years ago, sequencing technology has made enormous progress, significantly reducing time and complexity. Portable sequencing devices are now commercially available and have been fundamental, for example, for field-surveillance of Ebola virus in West Africa and rapid identification of SARS-CoV-2 (COVID19) variants.These portable devices are based on the motion of dissolved ions (charged atoms) through a tiny hole called a "nanopore", whose dimensions are in the order of a few nanometers, i.e. billionths of a metre. If DNA strands are present, they can also be made to flow through the pore, temporarily blocking the flow of ions. Each of the four bases forming the DNA modifies the ion flow in a slightly different way and therefore, by monitoring how the flow of ions changes over time it is possible to determine the sequence of the bases within the DNA. Nanopore sequencing is revolutionising the way we sequence DNA, but suffers from some limitations which are fundamentally linked to the ion current approach. In particular, although DNA can pass through the pore at a high speed (~1 million bases per second) it is not possible to monitor the motion of ions this quickly and therefore it is not possible to read the sequence in real time. Instead complex enzyme-based mechanisms must be used to slow down the DNA transit.In this project, we hope to achieve a transformative change in real-time sequencing rates by combining solid-state nanopores with a new way of identifying the four bases within DNA strands. To do so, we will use microwaves - electromagnetic waves oscillating at GHz frequencies. Microwaves are at the core of the information and communication technologies used in mobile phones, wi-fi and Bluetooth networks and GPS satellites to carry large amounts of information. Microwaves also interact with matter and can be used to probe molecules by measuring their unique electromagnetic fingerprints. Our proposed sensors will combine atomically-precise nanofabrication with the measurement accuracy offered by high frequency electronics. The device will consist of an atomically-thin conductor (graphene) shaped as a bowtie with a small gap at its centre. The conductor acts as a waveguide, enabling microwave propagation between the two ends of the sensor. The centre of the bowtie will be carefully aligned with a nanopore, so that, when DNA passes through the pore, it interacts with the electromagnetic field formed at the bowtie tips. We hope that each of the four bases forming the DNA (A, C, G and T) will cause different transmission and reflection of the propagating microwaves, allowing the sequence of bases to be read. This approach replaces the slow, ion-motion based electrochemistry currently used for nanopore sensing with fast communication-engineering technologies, with potential for a 1000-fold increase in speed.The sensor technology developed will have capabilities beyond sequencing, as it can be applied to analyse other molecules relevant for biochemistry and medicine. Thanks to the compatibility of our sensors with electronic chip fabrication technology and the ubiquitous use of microwave electronics for wireless communication, we envisage a seamless integration with already existing technology to realise portable sequencing and sensing tools.

DNA 是生命系统中将信息从父母传递给孩子的核酸。确定四个信息携带碱基的顺序（表示为 A、C、G、T）称为“测序”。这种测序是现代分子生物学和遗传流行病学的核心，在诊断和精准医学方面具有巨大的应用潜力。自大约 20 年前首次对人类基因组进行测序以来，测序技术取得了巨大进步，显着缩短了时间并降低了复杂性。便携式测序设备现已投入商业使用，并且对于西非埃博拉病毒的现场监测和 SARS-CoV-2 (COVID19) 变种的快速识别至关重要。这些便携式设备基于溶解离子的运动（带电原子）通过一个称为“纳米孔”的小孔，其尺寸约为几纳米，即十亿分之一米。如果存在 DNA 链，也可以使它们流过孔，暂时阻止离子的流动。形成 DNA 的四种碱基中的每一种都以稍微不同的方式改变离子流，因此，通过监测离子流如何随时间变化，可以确定 DNA 内碱基的序列。纳米孔测序正在彻底改变 DNA 测序方式，但也存在一些与离子电流方法根本相关的限制。特别是，尽管 DNA 可以高速（约每秒 100 万个碱基）穿过孔，但不可能如此快地监测离子的运动，因此不可能实时读取序列。相反，必须使用复杂的基于酶的机制来减缓 DNA 转运。在这个项目中，我们希望通过将固态纳米孔与识别 DNA 内四个碱基的新方法相结合，实现实时测序速率的革命性变化股。为此，我们将使用微波——以 GHz 频率振荡的电磁波。微波是信息和通信技术的核心，用于移动电话、Wi-Fi 和蓝牙网络以及 GPS 卫星，以承载大量信息。微波还与物质相互作用，可以通过测量分子独特的电磁指纹来探测分子。我们提出的传感器将原子级精度的纳米加工与高频电子器件提供的测量精度结合起来。该设备将由一个原子薄的导体（石墨烯）组成，其形状为领结，其中心有一个小间隙。该导体充当波导，使微波能够在传感器的两端之间传播。蝴蝶结的中心将与纳米孔仔细对齐，这样，当 DNA 通过纳米孔时，它就会与蝴蝶结尖端形成的电磁场相互作用。我们希望形成 DNA 的四个碱基（A、C、G 和 T）中的每一个都会引起传播微波的不同传输和反射，从而能够读取碱基序列。这种方法用快速通信工程技术取代了目前用于纳米孔传感的缓慢的、基于离子运动的电化学，速度有可能提高 1000 倍。所开发的传感器技术将具有测序之外的功能，因为它可以应用于分析与生物化学和医学相关的其他分子。由于我们的传感器与电子芯片制造技术的兼容性以及微波电子学在无线通信中的普遍使用，我们设想与现有技术无缝集成，以实现便携式测序和传感工具。