Nature：给你的基因动动手术——CRISPR走出实验室

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Nature：给你的基因动动手术——CRISPR走出实验室
9 p) z9 x2 G5 L' w; Y. `' g- g% t4 Q2013-12-23 来源：生物360 作者：koo
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未来，病人或许不需要通过服用药片来治疗疾病，而是选择“基因手术”——使用 CRISPR 这种创新性的基因编辑技术将有害的变异剪除并植入健康的 DNA 来治疗疾病。目前，已经有人看到了其中的商机，创办了公司来研发和推广这种基因编辑技术。
% p8 W- _4 c4 ?CRISPR 技术从实验室走向市场2 x7 e% F4 K% }7 D) J. U1 L# K/ }
在过去的一年内，一种能快速、方便有效地靶向人类基因组任何基因的新方法—— CRISPR 技术引起了科学界的广泛关注，成为全球科学家的新宠。遗传工程师、神经科学家甚至植物生物学家都将其看成是高效且精确的研究工具。现在，这套基因编辑系统已经催生了一家生物技术公司，引得众多投资人士纷纷抛出橄榄枝。
( G* o" j3 D8 R8 |位于马萨诸塞州剑桥市的 Editas Medicine 公司宣布于今年11月25日创立，该公司获得了 4300 万美元的风险投资启动资金。该公司由 5 名 CRISPR 研究领域的专家所创办，旨在研发直接修改与疾病有关的基因来治疗疾病的方法。
  e. e- f7 S4 K+ a: A: r该公司的临时负责人、风险投资商北极星投资公司的合伙人凯文•比特曼表示：“这是一个平台，或许会对各种各样的遗传疾病产生深远的影响。”, y# h6 D- N# F
最好的基因剪切技术
: o) i& F7 j, c4 U! V科学家们在研究中发现，细菌具备一种有高度适应性的免疫系统，使它们能发现并击退来自某种噬菌体的多次进攻，很多科学家据此意识到，细菌的免疫系统拥有一个非常有价值的特性：以某个特定的基因序列为目标。' h. q0 n. U  M: r
今年 1 月，4 个研究团队报告了这一被称为 CRISPR 的系统。细菌用这一策略来探测并剪除外来 DNA 。剪除 DNA 的酶 Cas9 会在一个 RNA 引导序列的帮助下发现目标。现在，研究人员可以借用基因工程方法，追踪任何基因。
6 q3 l8 Z! x& I6 D随后，许多科研团队利用这一系统来删除、添加、激活或抑制人体、老鼠、斑马鱼、细菌、果蝇、酵母、线虫和农作物细胞中的目标基因，从而证明了这个技术的广泛适用性。美国哈佛大学的乔治•彻奇说，生物学家最近研发了一些新方法来精确操纵基因，“但 CRISPR 的功效和易用性在各方面都更胜一筹”。
$ f. h" ?% i+ e7 i. o; A基于 CRISPR ，科学家构建人类疾病小鼠模型的速度要比之前快得多，研究单个基因则更为快速，能立刻方便地改变细胞中的多个基因，以便研究它们的相互作用。3 g: E. C1 B5 X$ E2 d

8 U6 V) A# c3 ~! ?# dEditas 公司联合创办人张锋0 }/ ], |2 M) O) Q
Editas 公司并没有透露其主要研究哪些疾病，不过，该公司的联合创办人之一、麻省理工学院（MIT）麦戈文脑研究所的神经科学家张锋（Feng Zhang，音译）表示，他们可能首先会对由单个错误的基因副本所导致的疾病进行研究。而要治疗与两个错误的基因副本有关的疾病更加麻烦，因此，可能需要更进一步的研究。
5 Q3 F" k2 y1 f0 k竞争对手也不容小觑; B% }; A3 N8 m/ k# |
传统的基因疗法一般使用病毒来递送 DNA ，这种方法能够引入有用的基因，但并不能改变错误的序列，因此并不精准。% l0 K* q! D& n4 ]6 R! Z
目前，在基因编辑技术领域“称王称霸”的是位于美国加州的桑加莫生物科技公司，该公司使用一套不同的系统（建立在锌指核酸酶的基础上）来剪除目标基因或让目标基因失效。很多公司表示，与锌指核酸酶系统相比， CRISPR 使用起来更加容易且可“量体裁衣”。但就目前情况来看，桑加莫生物科技公司的技术处于领先地位。该公司正使用锌指核酸酶破坏为一个细胞表面蛋白（HIV 借用这一蛋白进入人体的免疫细胞）编码的基因。
/ ~4 X! `9 M6 y6 u1 _桑加莫生物科技公司的首席技术馆菲利普•格里高利说：“ CRISPR 在学术界引起了暴风雨，但 CRISPR 仍然有几个问题需要解决。比如，有研究表明 Cas9 会在遗传组内的非目标位置进行剪切活动。”张峰也表示，他们正在想方设法增加酶的针对性，而且已初见成效。4 {* c2 c0 Q4 L0 k5 ^9 \; u! H
这两家公司都希望能获得美国食品和药物管理局（ FDA ）的批准。美国投资银行 Cowen and Company 的生物技术分析师尼可拉斯•毕肖普表示：“ FDA 从来没有批准过一种基因治疗产品。”此前，有科学家们进行了几例基于病毒的基因疗法，这些尝试刚开始都很高调，但最终死得很难看，导致基因治疗领域元气大伤，目前正处于缓慢的恢复期。毕肖普说：“目前，坚冰正在慢慢消融。”6 S6 r' ]8 l) X' |5 B) {
原文检索：
# X/ ?- D, j3 t' xHelen Shen. CRISPR technology leaps from lab to industry. Nature, 03 December 2013; doi:10.1038/nature.2013.14299
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zb_ming

CRISPR technology leaps from lab to industry: i2 k- P1 {0 j( G
Scientists launch company to develop the therapeutic potential of gene-snipping enzymes.6 O( d9 n2 q' ^6 y5 K0 M

6 n4 N" e: o" f# _+ hHelen Shen
+ S# o' T) X1 e# S- L03 December 2013
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Kent Dayton- ~( }, t3 n' g6 u6 V7 D% N9 w
Feng Zhang is one of the founders of Editas Medicine, which aims to use CRISPR gene-editing technology to treat disease.
) q% S3 b/ U% HInstead of taking prescription pills to treat their ailments, patients may one day opt for genetic 'surgery' — using an innovative gene-editing technology to snip out harmful mutations and swap in healthy DNA.
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  ]$ a1 k% h% Q" [& A7 z( U4 K+ ]Ten people who mattered in science this year
+ Z* t( {; Z! H8 B3 x- kWhy swine flu, and a vaccine against it, may have triggered cases of narcolepsy
# ?7 e% i, [( b; pBest evidence yet that our Universe is a hologram
& w5 t( X% y6 SThe system, called CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), has exploded in popularity in the past year, with genetic engineers, neuroscientists and even plant biologists viewing it as a highly efficient and precise research tool. Now, the gene-editing system has spun out a biotechnology company that is attracting attention from investors as well.6 D6 \  S' `8 w% r. K' J6 w, ?

5 O; Z% X( j5 y# KEditas Medicine, based in Cambridge, Massachusetts, announced its launch on 25 November with an initial US$43 million venture capital investment. The company, founded by five leading CRISPR researchers, aims to develop therapies that directly modify disease-related genes.% \- o& K: o* V6 O) m
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"This is a platform that could have a profound impact on a variety of genetic disorders," says interim president Kevin Bitterman, a venture capitalist at Polaris Partners in Waltham, Massachusetts, which is one of Editas' backers.2 E: b, i$ {2 D5 ~6 _
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The nicest cut1 g: }" A& T3 J. Q% g2 b
CRISPR piggybacks on an immune strategy that bacteria use to detect and chop up foreign DNA. The DNA-cutting enzyme Cas9 finds its target with the help of an RNA guide sequence that researchers can now engineer to home in on potentially any gene of interest.
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# O- z8 E" Q, OPrecision gene editing paves way for transgenic monkeys1 p# d: V1 K3 P: u6 K+ W
French institute prepares for gene-therapy push
* R# l6 N  @; i+ ^, n( ZGene-therapy enzymes make unpredicted errors# i5 [* F2 c% X* V
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6 v' q7 x& z4 q( ]Editas is not disclosing its intended targets, but the technology might be tried first on diseases caused by a single faulty gene copy, says Feng Zhang, a neuroscientist at the Massachusetts Institute of Technology’s McGovern Institute for Brain Research in Cambridge, Massachusetts, and one of Editas’ founders. Simply disabling the disease-causing copy could clear the way for the good copy to take over. Treating conditions involving two dysfunctional gene copies will require correcting the gene by splicing in healthy DNA — a feat that Zhang says will require more work and engineering.
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CRISPR competition1 s1 _0 j; M* R) M6 p- S4 @
Conventional gene-therapy approaches have used viruses to deliver DNA — a comparatively imprecise method that can introduce beneficial genes, but not change faulty sequences.
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" K  n5 Q) f: _; o2 fTargeted gene editing, of the kind Editas is attempting, has so far been dominated by one company: Sangamo BioSciences of Richmond, California. Sangamo uses a different system, based on zinc-finger nucleases, to snip and disable genes of interest. Many researchers say that CRISPR is easier to use and customize compared to zinc-finger nucleases, but Sangamo has a healthy head start over Editas. The company's clinical trials are showing encouraging results for using zinc-finger nucleases to disrupt the gene encoding a cell-surface protein that HIV uses to enter immune cells.7 Z3 C' p/ _5 N! R8 u& G

# \/ t( r1 k. \"CRISPR has taken the academic world by storm, and it's a very exciting new technology," says Philip Gregory, chief scientific officer of Sangamo. But, he says, there are still several kinks to be resolved, including studies that suggest that Cas9 can make cuts at off-target sites in the genome. Zhang says that his group and others are working on increasing the enzyme's specificity, and have already made some gains.
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: P- _& c. j2 T7 r( tEventually, both companies hope to secure the approval the US Food and Drug Administration (FDA). "The FDA has never approved a gene therapy product," says Nicholas Bishop, a biotechnology analyst at Cowen and Company in New York. The field has been slow to recover from a few high-profile, deadly failures of early virus-based gene therapy trials. But these days, says Bishop, "the regulatory climate is thawing considerably."
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Nature doi:10.1038/nature.2013.14299

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谢谢提供原文。