A biomolecular-design approach in synthetic biology: towards synthetic cytoskeletons

生物学为设计新的生物材料和功能系统提供了丰富的信息、材料和灵感。反过来，这些新实体可能会在从电子到医学的领域找到应用。我们对构建生物成分--蛋白质、细胞、组织等--的原理的理解还处于早期阶段；我们才刚刚开始挖掘这一知识的潜力。将生物的复杂性降低到原理和可管理的构件，然后将它们拼凑在一起形成新的材料和系统的努力被称为“合成生物学”。这是一门非常新的、令人兴奋的科学。然而，有一个问题：我们目前在这方面做得不是很好。天然生物系统主要由六种分子组成：碳水化合物、脂类、核酸、蛋白质、各种小分子和水。其中每一个都有自己的利基功能：水是溶剂；除其他外，小分子在整个生物中提供共同的能量货币和快速的信号传递手段；碳水化合物提供结构和可获得的能量来源；脂类形成包裹细胞和细胞内功能隔间的膜；以及核酸存储和传递信息以制造蛋白质、细胞等。我们把蛋白质留到最后，因为它们有些独特，因为它们执行无数功能：一些是结构性的，另一些是信号，许多作用于小分子，更多的仍然为我们的防御和免疫系统提供基础，等等。自然的一个关键特征是，它使用“自组装”将其组件组装在一起--即，上述生物分子以某种方式被编程为以精确的方式相互作用和合作--这与我们目前构建日常技术的方式截然不同。这项提议有两个广泛的目标：首先，我们的目标是降低大自然的复杂性，并创建一个生物灵感构建块的工具包，这将允许新的生物材料和功能系统进行编程和可靠的自组装。其次，我们将从拼凑构件开始，形成仿生系统，捕捉生物组装的关键特征，如蛋白质和细胞网络，尽管第一次是粗略的。我们研究的目标之一是被称为多肽的小蛋白质，这种蛋白质在实验室里可以相对容易地制造出来。我们希望从自然中了解某些多肽的不同化学成分如何指导它们形成定义明确的3D结构，许多生物学都建立在这些结构之上。这将需要研究天然的多肽，找到驱动它们折叠和自组装的“规则”。我们的第二个目标是脂膜。我们需要这些来帮助封装我们计划制造的蛋白质组件，我们需要封装，这样我们才能对我们目标产生的系统进行一些控制。这正是生物学使用封装的原因。为什么要做这一切？著名的物理学家理查德·费曼曾经说过，他不能建造的东西，他就不明白。这是我们在研究中采用的原则：我们计划观察自然生物系统，从中学习，然后通过设计和尝试构建新的简化系统来测试我们的理解。这并不容易，而且存在失败的风险。然而，潜在的回报是高的：我们至少可以了解生物学的一些组成部分是如何组装的；然后我们和其他人可以利用这种理解来创造新的生物材料、设备和系统，这些材料、设备和系统最终可能会在医学、电子和分析科学中得到应用。

Biology provides a wealth of information, materials and inspiration for engineering new biomaterials and functional systems. In turn, these new entities may find applications in areas from electronics through to medicine. It is early in the development of our understanding of the principles upon which biological components--proteins, cells, tissues etc--are built; and we are only just beginning to tap the potential of this knowledge. Endeavours to reduce biological complexity to principles and manageable building blocks, and then piece these together to form new materials and systems are known as 'synthetic biology'. This is a very new and exciting science. There's a catch, however: we're not very good at it at the moment. Natural biological systems largely comprise six types of molecule: carbohydrates, lipids, nucleic acids, proteins, a wide variety of 'small molecules' and water. Each of these have their own niche functions: water is the solvent; amongst other things, small molecules provide the common currency of energy and rapid means of signalling throughout biology; carbohydrates provide structure and accessible sources of energy; lipids form the membranes that wrap up cells and functional compartments within cells; and nucleic acids store and pass on the information to make proteins, cells and so on. We have left proteins until last as they are somewhat unique in that they perform a myriad of functions: some are structural, others signal, many act on small molecules, more still provide the basis of our defence and immune systems, and so on. A key feature of Nature is that it uses 'self-assembly' to piece its components together--i.e., the above biomolecules are somehow programmed to interact and cooperate in precise ways--which is very different from how our everyday technologies are currently built. This proposal has two broad aims: first, we aim to reduce the complexity of Nature and create a toolkit of bioinspired building blocks, which will allow the programmed and reliable self-assembly of new biomaterials and functional systems. Second, we will make a start at piecing the building blocks together to form biomimetic systems that capture the key features of biological assemblies such as networks of proteins and cells, albeit crudely in the first instance. One of the targets of our study are small proteins called peptides, which can be made in the lab relatively easily. We wish to learn from Nature how the different chemistries of certain peptides instructs them to form the well-defined 3D structures upon which much of biology is built. This will require examining natural peptides, finding 'rules' that drive their folding and self-assembly. Our second targets are the lipid membranes. We need these to help encapsulate the protein assemblies that we plan to make, and we need encapsulation so that we can gain some control over the systems that we aim to generate. This is precisely why biology uses encapsulation. Why do all of this? The famous physicist, Richard Feynman once remarked that what he could not build, he did not understand. This is the principle that we have adopted for our research: we plan to look at natural biological systems, learn from them, and then test our understanding by designing and attempting to construct new simplified systems. This will not be easy and there is a risk of failure. However, the potential rewards are high: we stand to learn how some of biology's components assemble at the very least; and this understanding can then be applied by us and by others to create new biomaterials, devices and systems that might eventually find applications in medicine, electronics and analytical science.