Personalized Clinical Diagnostics and Beyond: Integrated Ring Resonator Arrays

摘要 生物学的范式转变往往是由测量技术的创新催化的。基因组学 蛋白质组学给生物学带来了革命性的变化，但如果没有蛋白质组学的发展，就不可能实现这一点 毛细管测序、cDNA微阵列和质谱学等 技术。癌症生物学从分子水平的细节中受益匪浅 这些工具，允许阐明疾病发生和发展背后的许多扰动。 不幸的是，许多相同的测量方法不适用于临床环境和 因此，医生不能获得与美国医学会 院士。因此，尽管我们对癌症的分子基础有了更多的了解，但 转化为临床医学的工作严重滞后。这项提议描述了一位革命者 有可能深刻改变临床医学面貌的生物分析技术 以及更远的地方。极灵敏的集成微环谐振器的高密度阵列将允许 从单个患者样本中同时定量检测多个基因和蛋白质特征。 这项技术的显著特点包括：灵敏度，允许无聚合酶链式反应的基因和单一蛋白 检测、无标签和实时操作、超高可扩展性(50,000个传感器/cm2)、自动化 微流控操作，以及经商业验证的可制造性(通过与cmos兼容的工艺)。 为了展示这项技术的威力，我们将生成一个分子疾病指纹，允许 三种临床上难以区分但生化上截然不同的疾病途径的鉴别 致命性脑癌多形性胶质母细胞瘤的潜在原因。重要的是，这些途径中的每一个都是 已知对不同的治疗剂有效，因此个性化诊断相当于 个性化治疗。我们还将利用这一使能技术来深入了解 围绕转录后基因调控和分泌物内异质性的问题 个体免疫细胞的反应。这项技术有望广泛影响 生物医学科学，既满足了当今临床诊断的挑战，又开创了 改变未来范式的发现。

ABSTRACT Paradigm shifts in biology are often catalyzed by innovations in measurement technologies. Genomics and proteomics have revolutionized biology but would not have been possible without developments in capillary sequencing, cDNA microarrays, and mass spectrometry, amongst other enabling technologies. Cancer biology has significantly benefited from the molecular-level detail provided by these tools, allowing elucidation of many perturbations underlying disease onset and progression. Unfortunately, many of the same measurement approaches are not applicable in the clinical setting and thus physicians do not have access to the same detailed biochemical information enjoyed by the academician. As a result, despite our increased knowledge of the molecular bases of cancer, the translation to clinical medicine has lagged significantly behind. This proposal describes a revolutionary biological analysis technology which has the potential to profoundly change the face of clinical medicine and beyond. High density arrays of extraordinarily sensitive integrated microring resonators will allow many gene and protein signatures to be simultaneously quantitated from a single patient sample. Distinguishing features of this technology include: sensitivity allowing PCR-less gene and single protein detection, label-free and real time operation, ultra-high scalability (>50,000 sensors/cm2), automated microfluidic operation, and commercially validated manufacturability via CMOS-compatible processing. To demonstrate the power of this technology, we will generate a molecular disease fingerprint allowing differentiation between three clinically indistinguishable yet biochemically distinct disease pathways underlying the deadly brain cancer glioblastoma multiforme. Importantly, each of these pathways is known to respond effectively to different therapeutic agents, thus personalized diagnosis equates to personalized treatment. We will also utilize this enabling technology to provide insight into profound questions surrounding post-transcriptional gene regulation and heterogeneity within the secreted responses of individual immune cells. This technology promises to broadly impact the landscape of the biomedical sciences, both meeting the clinical diagnostic challenges of today and pioneering the paradigm-shifting discoveries of tomorrow.