Application of single cell genomics for precision medicine in myelodysplastic syndromes.

什么是骨髓增生异常综合征(MDS)？骨髓增生异常综合征(MDS)是一组血液疾病，骨髓不能正常工作，不能产生足够的健康血细胞。MDS患者可能会有许多问题，如贫血、出血和感染。大约每3名MDS患者中就有1人会患上更严重、更难治疗的白血病。大多数MDS患者的存活时间不超过3年，但这一点具有很高的变异性。目前，大多数MDS患者都接受了输血和抗生素治疗，这些药物可以缓解症状，但不能治愈疾病。目前，唯一可用的治疗方法是接受健康捐赠者的骨髓移植。我们如何诊断MDS？尽管新的治疗方法正在开发，但仍需解决的一大问题是我们更有效地诊断MDS的能力。为了诊断MDS，需要血液和骨髓样本。尽管我们对这些宝贵的患者样本进行了大量的测试，但我们仍然经常错过MDS的诊断或弄错MDS的类型。在牛津，在6年的时间里，我们无法在大约一半的可能患有MDS的患者中得到明确的诊断。我们如何提高MDS的诊断和分型？我想提高对MDS的诊断，以便我们能够正确地诊断，并尽快为患者提供所需的治疗。我认为我们可以通过利用新技术来做到这一点。我们每个细胞都有一套基因。基因是由DNA组成的，它们共同构成了指导手册，使我们体内的每个细胞都能发挥作用。在过去的十年里，科学家们详细研究了基因如何在单个细胞中发挥作用，以及它们有时是如何出现导致疾病的错误的。现在有一些技术可以让我们研究单个细胞的基因(称为单细胞基因组学)，包括单个骨髓细胞。这使得研究实验室的科学家能够真正了解MDS患者骨髓细胞中的哪些基因存在错误。在这笔赠款中，我想让患者可以使用这些新技术。如果临床医生能够使用这项技术来查看患者单个骨髓细胞的基因，他们将能够更准确地确定患者患有什么疾病，以及如何最好地治疗它。更好的诊断意味着更好的治疗。我该怎么办？作为MDS诊所的一名医生，我会与患者交谈，并邀请他们加入我们的研究。我们将从患者那里收集两种类型的信息：1.我们将在患者在我们诊所开始旅程的时候和稍后的固定地点收集详细的临床信息。我们将采集这些患者的血液和骨髓样本。我们将使用这些样本来执行已经可以用于诊断MDS的标准测试，但我们也将使用这些样本来测试允许我们读取单个患者细胞上的基因的新技术。我们将利用这些信息来试图了解我们检测到的基因错误与患者病情进展之间是否存在联系，以及他们患上了哪种类型的MDS。我们还将调查我们的新基因技术在诊断MDS方面是否比现有工具更好。为什么这项研究很重要？我们希望这项研究能够帮助改进目前对MDS的诊断测试，并捕捉到更多我们错过的患者。如果我们要尽早为患者提供最好的治疗，这是至关重要的。还有许多其他疾病是由基因错误引起的，这些错误没有利用新的基因组技术来改善患者护理。我们也希望我们的研究成果能被其他疾病的研究人员和临床医生所应用，这样我们的方法就可以帮助MDS以外的疾病的患者。

What are Myelodysplastic Syndromes (MDS)?Myelodysplastic syndromes (MDS) are a group of blood diseases where the bone marrow does not work properly and cannot make enough healthy blood cells. Patients with MDS can have a number of problems such as anaemia, bleeding, and infections. Around 1 in 3 patients with MDS will develop leukaemia which is more serious and very difficult to treat. Most patients with MDS do not survive more than 3 years, but this is highly variable. Currently most patients with MDS are given blood transfusions and antibiotics, which manage the symptoms but do not cure the disease. At present the only cure available is to receive a bone marrow transplant from a healthy donor. How do we diagnose MDS?While new treatments are being developed, one of the big issues that still needs to be addressed is our ability to diagnose MDS more effectively. In order to diagnose MDS, blood and bone marrow samples are needed. Although we perform a huge number of tests on these precious patient samples, we still often miss the diagnosis of MDS or get the type of MDS wrong. In Oxford, over a period of 6 years we were unable to get a clear diagnosis in around half of all patients referred with possible MDS. How can we improve the diagnosis and classification of MDS?I would like to improve the diagnosis of MDS so we can get it right and give patients the treatments they need as soon as possible. I think we can do this by taking advantage of new technologies. Each of our cells has a set of genes. Genes are made of DNA, and together form the instruction manual that allows each cell in our body to function. Over the last decade, scientists have investigated in a lot of detail how genes work in individual cells, and how sometimes they can have errors that lead to disease. There are now technologies that allow us to look at the genes of individual cells ( known as single cell genomics), including individual bone marrow cells. This is allowing scientists in research laboratories to really understand which genes have errors in the bone marrow cells of patients with MDS. In this grant, I want to make these new technologies available to patients. If clinicians were able to use this technology to look at the genes of individual bone marrow cells of patients, they would be able to determine much more accurately what disease patients have, and how best to treat it. Better diagnosis means better treatment.What will I do?As a doctor in the MDS clinic, I will talk to patients and invite them to join our study. We will collect two types of information from the patients:1. We will collect detailed clinical information from patients at the beginning of their journey in our clinic and at fixed points later on.2. We will collect blood and bone marrow samples from these patients. We will use these to perform the standard tests that are already available to diagnose MDS, but we will also use these samples to test the new technologies that allow us to read the genes on individual patient cells. We will use this information to try to understand if there is a connection between the errors in the genes that we detect and how patients progress in their disease, and which type of MDS they develop. We will also investigate whether our new genetic technologies are better at diagnosing MDS than the existing tools. Why is this research important?We hope that this research can help improve the current diagnostic tests for MDS and capture more of the patients we are missing. This is essential if we are to provide the best treatments as early as possible for patients. There are many other diseases that are caused by errors in the genes, which do not take advantage of new genomic technologies to improve patient care. We also hope that our research results will be applied by researchers and clinicians working in other diseases, so that our approach can help patients with diseases other than MDS.