Synthetic Biology facility at the MRC Laboratory of Molecular Biology

MRC 分子生物学实验室的合成生物学设施

• 批准号: BB/M000842/1
• 负责人: Hugh Pelham
• 金额: $ 251.02万
• 依托单位: MRC Centre Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM000842%2F1
• 关键词: Synthetic; Biology; facility; MRC; Laboratory

Living cells have genes made of DNA. DNA is a molecule comprising a string of bases of four different types, and the sequence of these bases in a gene directs the synthesis of a particular protein, which consists of a string of amino acids of twenty different types. Three bases encode one amino acid, this code being read by a cellular machine, the ribosome, which makes the protein. Some triplets do not encode amino acids, but act as stop signals. It is possible to engineer cells such that one of these stop triplets instead encodes a synthetic amino acid, which can have novel chemical properties. Genes can be chemically synthesised with any sequence, so by introducing the appropriate triplet proteins can be specified that have novel properties, such as an enzyme that can be turned on by light. Synthetic biology also allows the creation of new kinds of ribosome in bacteria, engineered to translate only particular synthetic genes, which can read four bases at a time instead of three, thus significantly expanding the range of new amino acids that can be encoded. This technology not only makes possible a wide range of experiments to study the functions of cells and organisms, but also allows the production of novel proteins for therapeutic or other use, such as antibodies with drugs attached at specific sites. Ultimately, such engineering could produce entirely new encoded polymers with many potential uses.DNA too can be altered in novel ways. By engineering the enzymes that copy DNA, it is possible to produce, in the test tube, "XNA" molecules that retain the double helical structure of DNA but are made from chemically different precursors, and hence have a different chemical structure that is resistant to natural and chemical degradation, and can have other novel properties. By making billions of variants of a short sequence of bases, one can select molecules that have a desirable property, such as inhibiting an enzyme or catalysing a reaction, copy them into DNA, and identify the particular sequence. These molecules can be chemically synthesised, and used as potential drugs or for many other purposes.The development of these technologies depends on the synthesis of novel DNA sequences and genes, and many sophisticated forms of analysis including mass spectrometry and advanced microscopy to determine the properties of the novel proteins and XNA molecules that result, and their effects on cells and organisms. This award will provide the advanced equipment required to automate gene synthesis, engineer new functions, and test the many different applications of the new technology.

活细胞有DNA构成的基因。DNA是由一串四种不同类型的碱基组成的分子，基因中这些碱基的序列指导一种特定蛋白质的合成，这种蛋白质由一串二十种不同类型的氨基酸组成。三个碱基编码一个氨基酸，这个编码被细胞机器——核糖体——读取，核糖体制造蛋白质。一些三胞胎不编码氨基酸，但作为停止信号。有可能对细胞进行工程改造，使其中一个停止三胞胎编码一种合成氨基酸，这种氨基酸可以具有新的化学特性。基因可以用任何序列进行化学合成，因此，通过引入适当的三联体，可以指定具有新特性的蛋白质，例如可以被光激活的酶。合成生物学还允许在细菌中创造新型核糖体，这些核糖体被设计成只翻译特定的合成基因，一次可以读取四个碱基，而不是三个碱基，从而大大扩展了可以编码的新氨基酸的范围。这项技术不仅使研究细胞和生物体功能的广泛实验成为可能，而且还允许生产用于治疗或其他用途的新蛋白质，例如在特定位点附着药物的抗体。最终，这种工程可以产生具有许多潜在用途的全新编码聚合物。DNA也可以以新的方式被改变。通过改造复制DNA的酶，有可能在试管中产生“XNA”分子，这种分子保留了DNA的双螺旋结构，但由化学上不同的前体组成，因此具有不同的化学结构，可以抵抗自然和化学降解，并具有其他新特性。通过制造数十亿个碱基短序列的变体，人们可以选择具有理想特性的分子，例如抑制酶或催化反应，将它们复制到DNA中，并识别特定的序列。这些分子可以化学合成，用作潜在的药物或许多其他用途。这些技术的发展依赖于新DNA序列和基因的合成，以及许多复杂的分析形式，包括质谱法和先进的显微镜，以确定新蛋白质和XNA分子的特性，以及它们对细胞和生物体的影响。该合同将提供自动化基因合成所需的先进设备，设计新功能，并测试新技术的许多不同应用。

项目成果

Biosynthesis and genetic encoding of phosphothreonine through parallel selection and deep sequencing.

• DOI: 10.1038/nmeth.4302
• 发表时间: 2017-07
• 期刊: Nature methods
• 影响因子: 48
• 作者: Zhang MS;Brunner SF;Huguenin-Dezot N;Liang AD;Schmied WH;Rogerson DT;Chin JW
• 通讯作者: Chin JW

Optimizing orthogonality

优化正交性

• DOI: 10.1038/s41557-018-0115-7
• 发表时间: 2018
• 期刊: Nature Chemistry
• 影响因子: 21.8
• 作者: Ngai W