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在2015年12月1日的文件照片中，麻省理工学院Broad研究所的Feng Zhang参加了在华盛顿举行的国家科学院人类基因编辑安全与伦理问题国际首脑会议的小组讨论会。科学家正在改变强大的基因编辑技术，希望有一天可以抗击疾病，而不会永久改变人的DNA。 In this Dec. 1, 2015 file photo, Feng Zhang of the Broad Institute of MIT participates in a panel discussion at the National Academy of Sciences international summit on the safety and ethics of human gene editing, in Washington. Scientists are altering a powerful gene-editing technology in hopes of one day fighting diseases without making permanent changes to people's DNA. (AP Photo/Susan Walsh) 麻省理工学院和哈佛大学研究所的Feng Zhang表示：“如果您编辑RNA，可以进行可逆治疗，对于副作用来说，重要的是基因编辑先驱，他的研究团队星期三在科学杂志上发表了新的报告。 称为CRISPR的基因组编辑技术彻底改变了科学研究。它是一种生物切割和粘贴工具，可让研究人员发现活细胞内的基因缺陷，并使用分子“剪刀”来剪除该位点，删除，修复或替换受影响的基因。 研究人员正在使用CRISPR来尝试改善作物，发展抗疟疾蚊子，在动物中生长可移植的器官，并开发有助于遗传疾病如镰状细胞或肌营养不良症的治疗方法。 医疗使用面临挑战。因为DNA的变化是永久的，意外地切断错误的斑点可能会导致持久的副作用。 DNA修复在某些细胞（如脑和肌肉细胞）中比在其他细胞（如血细胞）中更难实现，因此靶向RNA可能提供重要的替代方案，圣地亚哥加州大学教授Gene Yeo教授说，不参与星期三的学习。他的团队正在创建自己的RNA定位版本的CRISPR。 遗传缺陷会使细胞产生太多或太多的特定蛋白质而导致疾病，或者根本就没有发生这种疾病。 RNA，表达的DNA，携带基因的指示开始蛋白质制造过程。张解释说，编辑RNA的说明书应该导致蛋白质异常生成的临时修复。因为RNA随着时间的推移而降解，所以理论上的变化只会在使用治疗时持续。 CRISPR适用于在细菌中进化的系统的哺乳动物细胞中，并将其作为分子剪刀用作名为Cas9的酶。张氏团队检查了Cas蛋白家族中的亲属，发现一个可以靶向RNA的Cas13。研究人员设计了Cas13品种，因此它坚持RNA而不是切割它。然后，他们融合在另一种蛋白质上来编辑该位点，并在实验室菜中进行测试。 研究处于最早阶段，需要更多的工作才能在动物体内进行测试。 但是，正在使用不同的Cas方法来靶向RNA的圣地亚哥的Yeo赞扬了相互竞争的工作。“这真的告诉我们，许多Cas蛋白质可以真正结合RNA，”他说。 “聪明的事情是不断去尝试。” 英文报道来源： Scientists are altering a powerful gene-editing technology in hopes of one day fighting diseases without making permanent changes to people's DNA. The trick: Edit RNA instead, the messenger that carries a gene's instructions. "If you edit RNA, you can have a reversible therapy," important in case of side effects, said Feng Zhang of the Broad Institute of MIT and Harvard, a gene-editing pioneer whose team reported the new twist Wednesday in the journal Science. A genome editing technique called CRISPR has revolutionized scientific research. It's a biological cut-and-paste tool that lets researchers spot a gene defect inside living cells and use molecular "scissors" to snip that spot, either deleting, repairing or replacing the affected gene. Researchers are using CRISPR to try to improve crops, develop malaria-resistant mosquitoes, grow transplantable organs inside animals, and develop treatments that one day may help genetic diseases such as sickle cell or muscular dystrophy. There are challenges for medical use. Because a change to DNA is permanent, accidentally cutting the wrong spot could lead to lasting side effects. And DNA repair is harder to achieve in certain cells, such as brain and muscle cells, than in others, such as blood cells—so targeting RNA may offer an important alternative, said University of California, San Diego, professor Gene Yeo, who wasn't involved in Wednesday's study. His team is creating its own RNA-targeting version of CRISPR. Disease can occur when a genetic defect leaves cells making too little or too much of a particular protein, or not making it at all. RNA, a cousin of DNA, carries the gene's instructions to start the protein-making process. Editing RNA's instructions should result in temporary fixes to abnormal protein production, Zhang explained. Because RNA degrades over time, the changes theoretically would last only as long as the therapy was used. To starting figuring out how, researchers returned to nature. CRISPR was adapted for use in mammalian cells from a system that evolved in bacteria, and uses as its molecular scissors an enzyme named Cas9. Zhang's team examined relatives in the Cas protein family and found one, Cas13, that could target RNA instead. The researchers engineered a Cas13 variety so it sticks to RNA instead of cutting it. Then they fused on another protein to edit that spot, and tested it in lab dishes. The research is in its earliest stages, requiring more work before it even could be tested in animals.But San Diego's Yeo, who is using a different Cas approach to target RNA, praised the competing work. "It really tells us that many Cas proteins can truly bind RNA," he said. "The smart thing to do is to test a lot of them." 和此前CRISPR系统用于编辑DNA不同，张锋团队在普雷沃氏细菌（Prevotella）中找到了PspCas13b酶。这是Cas13酶家族中能使RNA失去活性的“佼佼者”，是潜在的RNA“剪刀”。但张锋团队赋予PspCas13b的“使命”不是去让RNA失活，相反的，他们设计了PspCas13b的“变体”。这个“变体”失去了“剪刀”的功能，但会牢牢地结合在特定的RNA片段上。同时，PspCas13b“变体”的搭档——ADAR2蛋白会将该片段上的腺嘌呤核苷（A）替换成次黄嘌呤核苷（I）。为何要做此替换？原来，鸟嘌呤核苷（G）突变为腺嘌呤核苷（A）时有发生，而这被认为和杜氏肌营养不良症、帕金森病等疾病密切相关。为了让“REPAIR”(“REPAIR”的基本元件是一种取名为PspCas13b的酶和ADAR2蛋白。“REPAIR”可高效地修复RNA的单个核苷，因不会改变DNA信息而更为安全，将为基础研究和临床治疗提供一个新的工具同时，张锋团队对其进行了优化，设计出“REPAIR2”版本，将在转录组中可检测到的脱靶次数从1.8万次降至20次。据介绍，“REPAIR2”对目标RNA的编辑效率为20%-40%，最高达到51%。为验证“REPAIR”系统在疾病治疗上的潜力，张锋团队人工合成了会造成范科尼贫血和X连锁性肾源性尿崩症的突变，并将这些突变引至人体细胞中，最后成功通过“REPAIR”在RNA层次上修复了致病突变。 欢迎点击「PaperRss」↑关注我们！ |
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