Technologies for an in-vitro carbon copy of lung disease

我们拟议的工作重点放在肺上，解决它如何维持粘液产生和清除的生理平衡的物理方面，这是任何空气传播感染的第一个障碍。慢性肺病可导致一种被称为慢性阻塞性肺疾病(COPD)的常见疾病，正如2020年广泛报道的那样，可能是由于身体对SARS-CoV-2等病毒的反应而引发的严重炎症过程所致。还有一些流行的遗传疾病会影响肺部。例如，囊性纤维化从根本上表现为患者出现呼吸道阻塞、慢性感染和随后的炎性肺损伤时粘液纤毛清除受损的问题。纤毛病是一种遗传疾病，会影响活动的纤毛细胞器本身。在所有这些疾病中，特定的病因与更广泛的肺器官的健康和功能之间存在相互作用，而且患者之间的差异非常大，而且知之甚少。如果有一种方法可以迅速而可靠地创建一个代表特定患者的模型系统，并根据他们的疾病状态来快速测试治疗方法，那么临床实践可能会更加有效。这意味着使用患者肺部的原代细胞、其驻留的巨噬细胞以及任何其他相关的感染/混合感染/微生物区系。然后，可以建立一个高保真的疾病模型，连同可以代表感兴趣的细胞外基质的支架，以及任何血管和几何/结构边界。显然，生命科学是时候不再相互孤立地研究病原体、宿主、干细胞等了。我们在这里提出的是一系列技术步骤，能够快速可靠地在严重疾病发生时创建某个器官的复制件(我们将重点放在肺部)，以便优化治疗。这与不断增加的普通测序管道非常吻合，一些医院的高通量设施能够将样本测序降至单细胞分辨率。我们的碳复制平台将重建相关的器官表型，并支持生理和物理读数以及分子读数。我们特别关注我们将提议开发的技术的可持续性(规模和成本)。

Our proposed work focuses on the lung, addressing physical aspects of how it maintains a physiological balance of mucus production and clearance, which is the first barrier to any airborne infection. Chronic lung disease can lead to development of a common condition known as chronic obstructive pulmonary disease (COPD) and, as reported widely in 2020, can result from the severe inflammatory processes triggered as the body responds to viruses such as SARS-Cov-2. There are also a number of prevalent genetic conditions that affect the lung. Cystic Fibrosis (CF), for example, manifests fundamentally as problem of impaired muco-ciliary clearance with patients developing airway obstruction, chronic infection, and subsequent inflammatory lung damage. Ciliopathies are genetic conditions that affect the motile cilia organelles themselves. In all these diseases, there is interplay between the specific cause of disease, and the health and function of the lung organ more broadly, and there is extremely large and poorly understood patient-to-patient variability. Clinical practice could be vastly more effective if there was a way to promptly and reliably create a model system that represented the particular patient, with their state of disease, and on which to rapidly test therapies. This means using the patient's primary cells from lungs, their resident macrophages, and any other relevant infection/co-infection/microbiota. A high fidelity disease model can then be built, together with scaffolds that can represent the extracellular matrix of interest, and any vasculature and geometric/structural boundaries. It is clearly time for life-sciences to move on from studying pathogens, hosts, stem cells, etc. each in isolation from each other. What we propose here are a series of technological steps in the direction of being able to rapidly and reliably, and without intensive labour, create a carbon copy of a certain organ (we will focus on lung) at the moment of serious disease, for the purpose of optimising treatment. This dovetails very well with increasing common pipelines of sequencing, with high throughput facilities in some hospital able to sequence samples down to single cell resolution. Our carbon copy platforms will recreate the relevant organ phenotypes, and enable physiological and physical readouts as well as molecular. We pay particular attention to the sustainability (scale and cost) of the technologies that we will propose to develop.