Nanopore-based Electrical Device for DNA Sequencing

用于 DNA 测序的纳米孔电子装置

• 批准号: 7938663
• 负责人: Gustavo Alejandro Stolovitzky
• 金额: $ 121.13万
• 依托单位: IBM THOMAS J. WATSON RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938663
• 关键词: Adverse reactions; Area; Base Sequence; Budgets; Caliber; Caring; Cells; Charge; Chemistry; Communities; Comparative Study; Complement; Computer Simulation; DNA; DNA Sequence; Data; Deposition; Development; Devices; Diploidy; Electrodes; Electronics; Engineering; Exercise; Film; Funding; Genes; Genome; Goals; Government Agencies; Health; Hour; Housing; Human Genome; Human Resources; Individual; Industry; Information Technology; Investments; Mainstreaming; Mechanics; Medical; Medical Research; Medicine; Metals; Methods; Nucleotides; Patients; Physiologic pulse; Positioning Attribute; Price; Process; Production; Proteins; Reading; Research; Resolution; Risk; Scientist; Semiconductors; Single-Stranded DNA; Site; Source; Speed; Supercomputing; System; Techniques; Technology; Time; Transistors; United States National Institutes of Health; Variant; Vertebral column; Work; base; cost; design; electric field; improved; inorganic phosphate; instrument; mammalian genome; models and simulation; molecular dynamics; nano; nanofluidic; nanometer; nanopore; sensor; tool; voltage; Adverse reactions; Area; Base Sequence; Budgets; Caliber; Caring; Cells; Charge; Chemistry; Communities; Comparative Study; Complement; Computer Simulation; DNA; DNA Sequence; Data; Deposition; Development; Devices; Diploidy; Electrodes; Electronics; Engineering; Exercise; Film; Funding; Genes; Genome; Goals; Government Agencies; Health; Hour; Housing; Human Genome; Human Resources; Individual; Industry; Information Technology; Investments; Mainstreaming; Mechanics; Medical; Medical Research; Medicine; Metals; Methods; Nucleotides; Patients; Physiologic pulse; Positioning Attribute; Price; Process; Production; Proteins; Reading; Research; Resolution; Risk; Scientist; Semiconductors; Single-Stranded DNA; Site; Source; Speed; Supercomputing; System; Techniques; Technology; Time; Transistors; United States National Institutes of Health; Variant; Vertebral column; Work; base; cost; design; electric field; improved; inorganic phosphate; instrument; mammalian genome; models and simulation; molecular dynamics; nano; nanofluidic; nanometer; nanopore; sensor; tool; voltage

DESCRIPTION (provided by applicant): The technologies that make sequencing DNA fast, cheap and widely available have the potential to revolutionize bio-medical research and herald the era of personalized medicine. Being able to sequence human genomes for $1000 will enable comparative studies of variations between individuals in both sickness and health. Ultimately it can improve the quality of medical care by identifying patients who will gain the greatest benefit from a particular medicine, and those who are most at risk of adverse reactions. Nanopore-based sequencing technologies attempt to thread a long DNA molecule through a few nanometer wide nanopore and use physical differences between the four base types to read the sequence of bases in DNA. The two major potential benefits of nanopore sequencing are the high speed and the low price. Nanopore sequencing does not need slow and expensive chemistry, therefore electrical-only sequence readout can proceed at highest rates achievable by modern electronics. At present, the nanopore sequencing is still a promise - no single nucleotide resolution has as yet been achieved experimentally. It is very likely that the ability to localize a DNA molecule inside a nanopore with a single base resolution would provide a sufficient time for read-out electronics to determine the base type. We propose a nano-electro-mechanical device (DNA Transistor) capable of controlling the translocation of a single DNA molecule inside a nanopore with single nucleotide accuracy. This function is based on interaction of discrete charges, localized on phosphate groups along the backbone of a DNA molecule, with the externally controlled electric field confined inside the nanopore. The design of the DNA Transistor relies on well researched thin film deposition techniques from semiconductors industry. The device is a stack of metal and dielectric layers, each a few atoms thin, with a nanopore penetrating through the stack. The electric potentials applied to the metal layers traps the DNA molecule inside the nanopore. Pulsing these potentials allows controlled translocation of the molecule with a single base resolution. IBM Research is uniquely positioned to implement the proposed idea. Our experimental effort will rely on in-house industry leading semiconductor device fabrication facilities. The experimental component of the effort will be complemented by a modeling and simulation component that will rely on in-house Blue Gene supercomputing capabilities. Our first aim is to fabricate the DNA transistor and demonstrate its capability to translocate the DNA molecule through the nanopore with a single base resolution. The second aim is to electrically differentiate bases of the localized DNA molecule. The final aim is to develop cost-effective DNA Transistor fabrication methods suitable for mass production. PUBLIC HEALTH RELEVANCE: IBM proposes the design, characterization and production of a nano-electro-mechanical device (the DNA Transistor) that forms the basis of a fast technology to sequence human genomes for $1000. The widespread availability of this technology will enable comparative studies of variations between individuals in both sickness and health. Ultimately it can improve the quality of medical care by identifying patients who will gain the greatest benefit from a particular medicine, and those who are most at risk of adverse reactions.

描述（由申请人提供）：使测序DNA快速，便宜且广泛可用的技术有可能革新生物医学研究，并预示了个性化医学时代。能够以1000美元的价格对人类基因组进行测序，将对疾病和健康中个体之间的变化进行比较研究。最终，它可以通过确定将从特定药物中获得最大收益的患者以及最有不良反应的风险来提高医疗保健的质量。基于纳米孔的测序技术试图通过几个纳米宽的纳米孔将长的DNA分子螺纹并使用四种基本类型之间的物理差异来读取DNA中的碱基序列。纳米孔测序的两个主要潜在好处是高速和低价。纳米孔测序不需要缓慢且昂贵的化学反应，因此仅电气序列读数可以以现代电子设备可实现的最高速度进行。目前，纳米孔测序仍然是一个希望 - 尚未通过实验实现单一的核苷酸分辨率。将DNA分子定位在具有单个碱基分辨率的纳米孔中的能力很可能会为读出电子设备确定基本类型提供足够的时间。我们提出了一个能够控制具有单核苷酸精度的纳米孔内部的纳米机电器械（DNA晶体管）。该函数基于离散电荷的相互作用，离散电荷的相互作用沿DNA分子的主链定位于磷酸基团，外部控制的电场限制在纳米孔内。 DNA晶体管的设计取决于半导体行业的经过良好研究的薄膜沉积技术。该设备是一堆金属和介电层，每个原子都稀薄，纳米孔穿过堆栈。应用于金属层的电势将DNA分子捕获纳米孔内的DNA分子。脉冲这些电势可以通过单个碱基分辨率控制分子的易位。 IBM研究是在实施拟议思想的独特位置。我们的实验工作将依靠内部行业领先的半导体装置制造设施。努力的实验组成部分将由建模和模拟组件进行补充，该组件将依赖内部蓝色基因超级计算功能。我们的第一个目的是制造DNA晶体管并证明其通过单个碱基分辨率通过纳米孔转移DNA分子的能力。第二个目的是电气区分局部DNA分子的碱基。最终目的是开发适合批量生产的具有成本效益的DNA晶体管制造方法。 公共卫生相关性：IBM提出了纳米机电设备（DNA晶体管）的设计，表征和生产，该设备构成了快速技术以$ 1000的序列人类基因组的基础。该技术的广泛可用性将使疾病和健康中个体之间的变化进行比较研究。最终，它可以通过确定将从特定药物中获得最大收益的患者以及最有不良反应的风险来提高医疗保健的质量。