An engineering platform for rapid prototyping synthetic genetic networks

合成生物学是一门令人兴奋的新学科，它为人类的健康和福利带来了许多好处。一个接近市场的例子是使用工程基因网络制造生物传感器，这种传感器可以快速检测毒素和有害微生物。然而，大多数合成生物系统都是基于活的转基因细胞，出于安全考虑和监管问题，它们不能在经过特别批准的实验室之外使用，而对生物传感器的最大需求尚未得到满足，即用于健康危害的使用点和护理点测试。詹姆斯·柯林斯教授的实验室最近报告了一项显著的突破，使用了基于干燥到纸条上的遗传成分的非生物系统。这些系统的准备成本非常低，可以长期稳定地储存，而且由于它们不是活的，也不能复制，它们不会对环境构成风险。因此，这项技术是进一步开发用于人类健康的传感器的理想选择。此外，这些无细胞系统可以非常迅速地大量准备，在几个小时内完成，并在几分钟内快速测试，而基于活细胞的系统可能需要数周准备和数天测试。这使得这项新技术成为基因电路“快速成型”的理想之选。许多设计可以快速产生和测试，最成功的设计然后可以用来产生基于细胞的系统，用于必要的应用，例如用于制造药物和其他有价值的化合物的工程代谢途径。在这个项目中，我们将进一步开发这些非凡的系统，并创造新的工具，使它们的设计和开发变得更加容易。首先，我们将创造新的计算工具，可用于设计多种应用的遗传电路。这些资料将在网上提供，以造福于研究界。其次，我们将建立快速自动化组装和测试新电路的方法，允许在非常短的时间内用最少的人力产生和测试数千种变体。第三，我们将寻求改进基础技术，提高无细胞设备的性能，并与我们开发的传感器一起开发低成本、易于现场使用的开源电子阅读器。第四，我们将通过产生能够快速和灵敏地检测各种外部输入的传感器来证明该技术的有效性。我们所有的新发明都将提供给研究界。除了上面提到的其他优点外，这项技术还使用户只需使用标准方案将适当的DNA成分添加到基本混合物中，就可以轻松地开发自己的分析方法。这样的设备可以非常大规模地廉价制造和分发。与低成本阅读器、配备GPS和时间数据的无处不在的移动设备以及云计算相结合，这将提供以前所未有的速度和细节检测健康危害的可能性，对人类健康和福利可能产生巨大影响。此外，这些设备非常适合用于教育，允许用户设计和测试自己的基因电路，而不会出现使用活细胞所固有的问题。出于这些原因，我们的建议提供了巨大的好处，并代表着合成生物学在现实世界中的适用性的一步改变。

Synthetic biology is an exciting new discipline which offers the potential to bring many benefits to human health and welfare. One near-market example is the use of engineered genetic networks to make biological sensors, or biosensors, which can rapidly detect toxins and harmful microorganisms. However, most synthetic biology systems are based on living genetically modified cells, and due to safety concerns and regulatory issues, they can not be used outside of a specially approved laboratory, whereas the greatest unmet need for biosensors is in the field, for 'point-of-use' and 'point-of-care' tests for health hazards. The laboratory of Professor James Collins recently reported a remarkable breakthrough, using non-living biological systems based on genetic components dried onto strips of paper. These systems can be prepared very cheaply, can be stored stably for long periods, and, since they are not alive and can not replicate, they pose no risks to the environment. This technology is therefore ideal for further development of sensors for human health. In addition, these cell-free systems can be prepared in large numbers very rapidly, in a matter of hours, and tested rapidly, in a matter of minutes, whereas living cell based systems may take weeks to prepare and days to test. This makes the new technology ideal for 'rapid prototyping' of genetic circuits. Many designs can be rapidly generated and tested, and the most successful can then be used to generate cell-based systems for applications where this is required, such as engineered metabolic pathways for manufacturing pharmaceuticals and other valuable compounds. In this project, we will further develop these remarkable systems and create new tools which will make it even easier to design and develop them. Firstly, we will create new computational tools which can be used to design genetic circuits for many applications. These will be made available on-line for the benefit of the research community. Secondly, we will establish methods for rapid automated assembly and testing of new circuits, allowing many thousands of variants to be generated and tested in a very short time with minimal human effort. Thirdly, we will seek to improve the basic technology, to improve the performance of the cell-free devices, and also develop low cost open-source electronic readers which can easily be used in the field along with the sensors we develop. Fourthly, we will demonstrate the usefulness of the technology by generating sensors which can rapidly and sensitively detect various external inputs. All of our new inventions will be made available to the research community. In addition to the other advantages mentioned above, this technology also makes it easy for users to develop their own assays simply by adding appropriate DNA components to a basic mixture, using standard protocols. Such devices can be manufactured and distributed cheaply on a very large scale. In conjunction with low-cost readers, ubiquitous mobile devices equipped with GPS and time data, and cloud-computing, this will offer the possibility to detect health hazards with unprecedented levels of speed and detail, with potentially huge effects on human health and welfare. Furthermore, these devices are ideal for use in education, allowing users to design and test their own genetic circuits without the issues inherent in using living cells. For these reasons, our proposal offers tremendous benefits and represents a step change in the real-word applicability of synthetic biology.