Subcellular spatial molecular imager for in-situ hi-plex multi-omic analysis of biological tissue specimens

研究背景在17世纪，显微镜的先驱创造了“细胞”一词来描述在放大镜下观察到的结构; 400年后，这个词和概念仍然存在。事实上，我们对“细胞理论”的理解支撑着健康和疾病的各个方面，从免疫细胞制造抗病毒抗体，到神经元储存记忆。要真正了解像大脑这样复杂的器官，不仅要对组成它的细胞类型进行普查，还要对它们的功能进行普查。以前，为了测量哪些基因被“打开或关闭”，组织样本必须在分析之前消化，因此“疾病战场”上患病组织或免疫细胞位置的“地理”丢失。我们意识到，同一个细胞可能具有完全不同的作用，这取决于它在器官或病变组织（如癌症）中的位置。这一想法是空间生物学概念的基础。从本质上讲，细胞所处的环境如何影响它的行为，它如何影响周围的细胞，这些信息能否帮助我们了解疾病的进展或对治疗的反应？此外，了解基因在细胞中的位置的重要性也越来越明显（细胞核，细胞膜，细胞质），因为这可能会影响它的作用。总体目标我们计划使用一种新的分子显微镜（CosMx空间分子成像仪）使用真实的-我们将生成非常详细的“空间地图”，提供组织标本中每个正常细胞、免疫细胞和病变细胞的类型和位置信息。我们将发现这个免疫系统“图谱”中的细胞如何在健康和患病组织中相互作用。我们将把显微镜聚焦到更高的分辨率，以研究细胞内基因和蛋白质的位置，为人类疾病提供真正新颖的发现。我们将研究“癌症免疫战场”，在：位置，活动，免疫细胞和癌细胞之间的相互关系，以确定如何靶向免疫系统可以帮助更多的癌症患者？我们的目标是将该技术安置在一个中央设施中，使所有专业的研究人员能够研究各种疾病，并回答以下问题：-为什么类风湿关节炎的治疗方法不适用于所有患者？-像COVID 19这样的感染对不同器官的免疫系统有什么影响？免疫系统如何导致大脑的退行性变化？疟疾寄生虫如何与血管相互作用？潜在的应用和好处这种分子显微镜技术的潜在应用是巨大的。由于在普通玻璃显微镜载玻片上研究真实世界的组织，它使我们能够解锁疾病的组织档案，并以令人难以置信的细节进行调查，以发现可以帮助未来患者的发现。它对癌症、自身免疫性疾病、感染以及器官正常发育的研究都有着广泛的意义。这项技术可能会影响病理学家的实践，因为与传统的组织“视觉”分析不同，现在可以进行全面的分子组织探索，不仅可以识别存在的每一个细胞，还可以测量其活性。重要的是，这些广泛而详细的分析可以在患者的小活检中进行，从而产生大量的信息，这些信息可以在未来指导患者从诊断时开始接受什么样的治疗。总的来说，这项技术有潜力为精确医疗策略的发展奠定基础，为许多疾病，特别是癌症，在正确的时间为正确的患者提供正确的治疗。

CONTEXT OF RESEARCHIn the 1600s pioneers of the microscope, coined the term 'cell' to describe structures observed under magnification; 400 years later, the word and concept remains. Indeed, our understanding of 'cell theory' underpins every aspect of health and disease, from immune cells making antibodies against viruses, or neurons storing memories. To truly understand a complex organ such as the brain it is imperative to have a census not only of cell types that compose it, but also their functions. Previously, to measure which genes were 'switched-on or off', tissue samples had to be digested before analysis and so 'geography' of position of diseased tissue or immune cells on the disease battlefield' was lost.We are realising that the same cell may have a completely different role depending on its position in an organ or diseased tissue like cancer. This idea underpins the concept of spatial biology. In essence how does the environment that cell resides in impact what it does, how does it influence surrounding cells, and can this information help us understand how a disease might progress or respond to treatment? Furthermore, it is becoming apparent of the importance of knowing where in the cell the gene resides (nucleus, membrane, cytoplasm) as this may impact what role it has.OVERALL AIMWe plan to use a novel molecular microscope (CosMx Spatial Molecular Imager) to measure exact 3-dimensional location of thousands of genes and protein molecules simultaneously within a cell using real-world sections of human tissue while maintaining the tissue architecture.OBJECTIVES-We will generate incredibly detailed 'Spatial Maps' providing information on type and location of every normal cell, immune cell and diseased cell in a tissue specimen.-We will discover how cells in this immune system 'atlas' interact in healthy and diseased tissues.-We will focus the microscope to even higher resolutions to study the position of genes and proteins within cell compartments providing truly novel discovery in human disease.-We will study the 'cancer immune battlefield', in terms of: Location, Activity, Inter-relationships between the immune cells and cancer cells to identify how targeting the immune system could help more patients with cancer?Our objective is for the technology to be housed in a central facility to enable access for researchers from all specialties to study a wide spectrum of diseases and allowing answers to questions such as:-Why do therapies for rheumatoid arthritis not work for all patients?-What impact do infections like COVID19 have on the immune system in different organs?-How the immune system lead to degenerative changes in the brain?-How malarial parasites interact with blood vessels?POTENTIAL APPLICATIONS AND BENEFITSThe potential applications of this molecular microscope technology are vast. As a result of studying real-world tissue on normal glass microscope slides, it allows us to unlock tissue archives of diseases and investigate with incredible detail to make discovery that could help future patients. It has implications for a broad range of diseases from cancer, autoimmune, infection as well as study of the normal development of organs.This technology could impact upon how pathologists practice as rather than traditional 'visual' analysis of tissue, a comprehensive, molecular tissue exploration is now possible enabling every cell present to be not only identified but also to have its activity measured. Importantly these broad and detailed analysis can be performed in small biopsies from patients resulting in huge amounts of information that could in the future guide what therapy a patient receives from the time of diagnosis.Overall, this technology has potential to lay the foundation of the development of a precision medicine strategy providing the right treatment for the right patient at the right time for many diseases in particular cancer.