Synthetic Biologic Application to T-cell Engineering

T效应细胞（T细胞）是免疫细胞，其主要作用是监视和破坏病毒感染的细胞。这些细胞能够归巢到感染部位，在那里它们离开脉管系统，分裂并杀死感染的细胞，但不伤害未感染的细胞。长期以来，我们一直在寻求利用它们的潜力和极端的选择性用于治疗目的。T细胞可以很容易地从血液中获得，并在体外培养和扩增。此外，有可能在体外选择性扩增对特定病毒特异的T细胞。这些特定T细胞群的施用对于某些罕见的病毒驱动的癌症是非常有效和无毒的治疗。然而，直到最近，如果不是不可能的话，也很难选择和扩增对更常见的癌症特异性的T细胞群，因为癌细胞与病毒感染的细胞不同，不含有外源蛋白。为基因治疗开发的基因载体技术为我们提供了一个根本性的解决方案：通过引入一种编码人工受体的新基因，我们可以很容易地产生大量对任何抗原具有特异性的T细胞。这种使用基因工程T细胞作为医学疗法的方法，已经被我们和其他人在早期临床研究中进行了测试，前景广阔。然而，T细胞工程领域仍处于起步阶段。通常情况下，我们将一个新基因引入T细胞，引起一个简单的变化，如特异性的改变。虽然已经制造了一系列不同的工程组件，例如触发归巢到某些组织，诱导增强的增殖等，但这些组件彼此不互连。此外，它们还没有得到很好的表征--例如触发阈值、信号动态范围等可能未知。这意味着T细胞工程效率低下，主要依赖于试错。最后，在目前的状态下，工程化T细胞具有非常复杂的新行为的巨大潜力无法实现。合成生物学是科学与工程相结合的生物学研究新领域。它试图通过应用在电子工程中主要发展的原理来形式化自然界中没有发现的复杂生物系统的工程。我们认为，合乎逻辑的下一步是将T细胞工程带入合成生物学时代。为了实现这一目标，我们计划：（1）生成一套先进的可相互连接的T细胞工程组件（部件）;（2）详细描述它们的动态功能特征;（3）构建一个完整的T细胞工程组件（部件）。一旦其中一些部件被构造和表征，我们将申请其他资金来开发数字方法，以模拟从组合开发的系统这些组件。这将使我们能够首先在计算机上开发基于这些模型的复杂系统，然后在现实中开发。通过这项工作，我们希望将T细胞工程领域推进到合成生物学时代。我们预计，我们将能够创造基于经过大量工程改造的T细胞的先进疗法，从而开创一个全新的治疗领域。

T-effector cells (T-cells) are immune cells whose major role is surveillance for and destruction of virally infected cells. These cells are capable of homing to the sites of infection where they exit the vasculature, divide and kill infected cells but leave uninfected cells unharmed. We have long sought to harness their potency and extreme selectivity for therapeutic purposes.T-cells can be easily obtained from blood and cultured and expanded in vitro. Further, it has been possible to selectively expand T-cells specific for a particular virus in vitro. Administration of these specific T-cell populations are remarkably effective and non-toxic treatments for certain rare virally driven cancers. Until recently however, it has been difficult if not impossible to select and expand T-cell populations specific for more common cancers since cancer cells, unlike virally infected cells do not contain foreign proteins. Gene vector technology developed for gene-therapy have allowed us a radically solution: By introducing a new gene coding for an artificial receptor, we can easily generate large populations of T-cells specific for any antigen. This approach of using genetically engineered T-cells as a medical therapy, has been tested by us and others in early clinical studies with much promise.The T-cell engineering field however is still in its infancy. Typically, we introduce a single new gene into T-cells to cause a simple change such as an alteration of specificity. Although a range of different engineering components have been made for example triggering homing to certain tissues, inducing enhanced proliferation etc. these components do not interconnect with each other. In addition, they are not well characterized - for instance triggering thresholds, dynamic range of signalling etc might be unknown. This means that T-cell engineering is inefficient, relying largely on trial error. Finally, in its current state, the tremendous potential of engineering T-cells with very complex new behaviours cannot be realized. Synthetic biology is a new area of biological research that combines science and engineering. It attempts to formalize the engineering of complex biological systems not found in nature by applying principles developed largely in electronic engineering. We believe the logical next step is to bring T-cell engineering into the synthetic biology era.To achieve this, we plan the following: (1) generate a set of advanced inter-connectible T-cell engineering components (parts); (2) characterize their dynamic functional characteristics in detail; Once some of these parts are constructed and characterised we will apply for other funding to develop numeric methods to model systems developed from combinations of these components. This will allow us to develop complex systems based on these models first in silico, then in actuality.with this work, we hope to advance the T-cell engineering field into the synthetic biology era. We anticipate that we will be able to then create advanced therapies based on heavily engineered T-cells leading to an entirely new field of therapeutics.