T-max: maximising insights from severe combined immunodeficiency and related disorders

T淋巴细胞（T细胞）是一种特殊类型的白细胞，对人体免疫系统至关重要。我们之所以知道这一点，部分是因为那些不幸出生时没有T细胞的婴儿会患上严重的感染，而这些感染对健康儿童几乎没有影响。这种非常罕见的疾病被称为严重联合免疫缺陷（SCID），在20世纪60年代末骨髓移植技术发展之前，它一直被视为死刑。如今，干细胞移植可以挽救大多数这些孩子，只要他们的病情在感染发生之前被识别出来。出于这个原因，我们现在开始对新生儿进行SCID筛查，使用一种测试，同时对一周大时已经收集的干血点进行其他筛查。如果T细胞数量低，婴儿会接受进一步的检测和治疗，以保护他们免受感染，直到免疫系统恢复正常。通常，出生时T细胞水平低是因为我们的一个基因存在拼写错误。由DNA组成的基因提供了制造单个蛋白质的指令。在SCID中，单个基因的错误意味着T细胞缺少了一种不可或缺的蛋白质。结果，T细胞不能正常发育，导致免疫系统衰竭。科学家们通过研究这一过程可能出错的多种方式，对健康T细胞是如何发育的有了很多了解。事实证明，许多不同基因的拼写错误可以阻止T细胞的发育。部分原因是T细胞以如此惊人的方式发育！确切地知道是哪个基因出错导致了新的SCID病例是非常有帮助的。它指导病人的治疗方式，而且，它使预测家庭中未来怀孕的风险成为可能。有时，科学家已经能够设计出不需要干细胞移植就能替代缺失部分的方法，例如在某些情况下通过基因治疗或酶替代。这些聪明的治疗依赖于确切地知道哪个基因出了问题，因为那是需要被替换的基因。令人沮丧的是，即使使用非常现代的基因组测序技术，大约十分之一的SCID病例也无法从基因上解释。在这个研究项目中，我们将试图弄清为什么T细胞在那里发育失败，以及我们可能对此能做些什么。其中一些患者可能在“旧的”SCID基因中有新的拼写错误，可能隐藏在有能力关闭邻近基因的DNA部分中。为了让我们有更好的机会找到这些，我们将使用新的和强大的方法来读取DNA分子，更广泛地观察每个SCID基因，并检查患者骨髓细胞中的基因是否开启或关闭。还有一些患者的新基因会出现拼写错误，而这些新基因以前与SCID没有关联——它们不在任何教科书的列表中。通过筛选过去SCID患者的拼写错误，我们已经找到了一些强有力的候选者。我们还有更多的工作要做，以了解为什么受影响的基因对T细胞如此重要，因为它们在许多其他组织中也很活跃。为了提供帮助，我们将在试管中研究细胞中的每个拼写错误，并找出它是如何扰乱相关蛋白质的结构和功能的。我们还将研究相同基因中的相同拼写错误是否会导致小鼠版SCID。如果我们能确定这些事情，我们就会了解到关于T细胞如何工作的一些新的和重要的东西。我们应该能更好地在未来的婴儿身上诊断出同样类型的SCID，并为他们的父母提供答案。我们和其他人将努力寻找新的更好的方法来挽救T细胞的发育，而不需要干细胞移植。

T lymphocytes (T cells) are a special type of white blood cell that is crucial to the human immune system. We know this partly because babies who are unlucky enough to be born without T cells get terribly sick with infections that barely affect healthy children. This very rare condition, called severe combined immunodeficiency ("SCID"), used to be a death sentence until the development of bone marrow transplantation from the late 1960s onwards. Nowadays, stem cell transplantation can save most of these children, as long as their condition is recognised before infection takes hold. For this reason, we now are starting to screen newborn babies for SCID using a test carried out alongside other screens on the dried blood spot already collected at a week of age. If T cell numbers are low, babies undergo further testing and treatment to protect them from infection until the immune system can be put right. Usually, being born with low levels of T cells happens because of spelling mistakes in one of our genes. Genes, which are made of DNA, provide the instructions to make individual proteins. In SCID, mistakes in a single gene mean that T cells are missing a protein they can't do without. As a result, the T cells can't develop properly, leaving the immune system depleted. Scientists have worked out a lot about how healthy T cells develop from studying the many ways this process can go wrong. It turns out that spelling mistakes in many different genes can prevent T cells from developing. This is partly because T cells develop in such a remarkable way! It can be very helpful to know exactly which gene has gone wrong to cause a new case of SCID. It guides the way a patient is treated and furthermore, makes it possible to predict the risk to future pregnancies within the family. Sometimes scientists have been able to design ways of replacing the missing part without a stem cell transplant, for instance by gene therapy or enzyme replacement in some cases. These types of clever treatment rely on knowing exactly which gene has gone wrong, since that is the one that needs to be replaced.It's frustrating then that around 1 in 10 cases of SCID can't be explained genetically, even using the very modern technique of genome sequencing. In this research project, we will try to get to the bottom of why T cell development fails there and what we might be able to do about it. Some of these patients might have new sorts of spelling mistakes in "old" SCID genes, perhaps hidden in parts of the DNA that have the power to turn off neighbouring genes. To give us a better chance of finding these we will look more widely around each SCID gene using new and powerful ways of reading along DNA molecules, and check whether genes are turned on or off in patient's bone marrow cells. Other patients will have spelling mistakes in new genes that haven't been linked to SCID before - they aren't on any textbook list. We have already found some strong candidates by screening for spelling mistakes in past patients with SCID. We have more work to do to understand why the affected genes are so important for T cells, because they are active in lots of other tissues too. To help, we will study each spelling mistake in cells in the test tube, and find out how it disturbs the structure and function of the related protein. We also will study whether the same spelling mistakes in the same genes can cause the mouse version of SCID. If we can be sure of these things, we will have learned something new and important about how T cells work. We should be in a better position to diagnose the same sort of SCID in future babies and provide answers to their mums and dads. We and others will be working hard to find new and better ways to rescue T cell development without a stem cell transplant.