H********g
发帖数: 43926 | 1 【 以下文字转载自 Military 讨论区 】
发信人: niuheliang (别问我是谁), 信区: Military
标 题: 同行评论文章显示贺建奎教授的重大贡献和不为人知的高超技巧
发信站: BBS 未名空间站 (Tue Apr 30 20:49:15 2019, 美东)
From 科研圈 科研圈 Today
今日凌晨，两位中国学者在 PLOS Biology 发表观点文章，对贺建奎基因编辑婴儿事件
进行学术性评论。这是 2018 年 11 月底贺建奎公布基因编辑婴儿诞生后，中国学者首
次从科学原理、实验设计和数据的角度，在学术期刊上发表正式同行评议文章。
文章的两位作者均为活跃在基因编辑领域的学者。。。两人都是胚胎基因编辑方面的专
家，多次在 Cell、Nature Biotechnology、Cell Research 等重要期刊发表论文。
。。。
贺建奎开始给人类胚胎实施显微注射。根据他的数据和之前的研究， 用 Cas9 蛋白代
替 Cas9 mRNA，在减数第二次分裂中期（metaphase II, MII）注射进胚胎能够减少嵌
合体的比例，但并不能完全避免嵌合现象发生[11，12]。而且这种策略只在 NHEJ 介导
的基因敲除中有用，对于 HDR 介导的精确基因修复则不然。虽然目前已经出现了很多
在细胞水平增强 HDR 修复的方法[13]，但是这些方法能否用于人类胚胎还是个未知数。
Mitalipov 课题组的研究显示母源等位基因是修复过程的模板，能够修正病理性突变[
12]。但其他课题组并不同意这一观点：Cas9 可能会导致大范围的碱基删除或重排，而
且导致以 PCR 为基础的基因分型检测得到假阳性结果（译者注：这里的假阳性意味着
实际上没有被成功编辑的基因，但在检测过程中被认为成功达到了编辑目的）[14]。上
述争论传达了这样的事实：目前学界对于 DNA 修复机制、人类早期胚胎基因编辑的后
果的理解仍然不全面，也反映出贺很可能低估了嵌合体的发生率，也低估了基因改造带
来的风险。
贺进一步宣称，他对 19 个经过编辑的人类囊胚的植入前遗传诊断（preimplantation
genetic diagnosis , PGD）样本进行了单细胞全基因组测序，以评估基因编辑的中靶
（on-target）和脱靶情况，然后才决定哪些胚胎可以植入母体。19 个胚胎中有 12 个
含有 CCR5 野生型等位基因，表明 CCR5 在这些胚胎中未得到完全编辑。重要的是，目
前还没有成熟可靠的单细胞全基因组测序技术能够评估脱靶突变 [16]。。。此外，嵌
合体问题也是一个重要的顾虑，这无法通过 PGD 来评估，因为我们无法对一个胚胎中
的所有细胞进行测序 [17]。这意味着即使被测序的细胞得到了正确的编辑，不可忽视
的风险仍然存在——胚胎中的其他细胞可能没有经过编辑，或携带预期外的突变，从而
导致无法预测的后果。
。。。
在两名女婴诞生后，贺的团队从脐带血、脐带和胎盘中采集了 DNA，进行全基因组测序
，并宣布 CCR5 编辑成功。全基因组测序结果显示，这些样本中各只存在两种不同的
CCR5 等位基因。分别占测序结果的大约一半。对于露露，一个等位基因保留了野生型
，而另一个等位基因出现了非移码删除（in-frame deletion，少了 15 个碱基。译者
注：即刚好有 5 个三联密码子被删除，因此其他未被删除的基因所表达的蛋白不会发
生改变）。对于娜娜，在全部测序结果中，CCR5 的靶位区域都出现了两个 CCR5 等位
基因突变，这表明娜娜的所有样本都没有受到母亲身体组织（其中含有 CCR5 野生型等
位基因）的污染，这点实在令人惊异。 | H********g
发帖数: 43926 | 2 Bear
niuheliang (别问我是谁)
2 76.* 4/30/19, 8:55:2 PM (42'7")
以上科研术语用人话说就是：
贺建奎教授
1、解决了长期以来专业权威们对基因技术能否应用于人的争论。
2、拥有专业权威们所不知道的测序技巧，包括嵌合体测序技巧。因此
3、虽然只有数量很少的胚胎也得到“令人惊异”的成功
Bear
lubbock12 (非老非小将)
3 157.* 4/30/19, 8:57:19 PM (39'50")
贺教授也要平反了
和韩春雨 张峰一起走上诺贝尔领奖台
Bear
WCNMLGB (CCC)
4 98.* 4/30/19, 9:1:5 PM (36'4")
niuheliang (别问我是谁)
以上科研术语用人话说就是：
贺建奎教授
1、解决了长期以来专业权威们对基因技术能否应用于人的争论。
2、拥有专业权威们所不知道的测序技巧，包括嵌合体测序技巧。因此
3、虽然只有数量很少的胚胎也得到“令人惊异”的成功
此主题相关图片如下：
删除
此主题相关图片如下：
删除
Bear
WCNMLGB (CCC)
5 98.* 4/30/19, 9:1:17 PM (35'52")
Substandard, Superficial, and Absurd: Experts Slam the Science Behind the
CRISPR Baby Experiment
A pair of genetic experts are claiming that the controversial human gene-
editing experiment conducted by Chinese scientist He Jiankui was not only
unethical, it was also deeply flawed from a scientific perspective. The
experiment, they said, likely won’t work as intended, and the two girls
produced by the project now face uncertain health risks.
The authors of the new PLOS Biology commentary article, geneticists Wang
Haoyi and Yang Hui from the Chinese Academy of Sciences (CAS), did not mince
words as they offered a severe rebuke of the gene-editing experiment
conducted by Chinese geneticist He Jiankui.
“[We] believe there is no sound scientific reason to perform this type of
gene editing on the human germline, and that the behavior of He and his team
represents a gross violation of both the Chinese regulations and the
consensus reached by the international science community,” wrote the
authors. “We strongly condemn their actions as extremely irresponsible,
both scientifically and ethically.”
At the Second International Summit of Gene Editing held in Hong Kong this
past November, He, an associate professor from Southern University of
Science and Technology, shocked the world by announcing the birth of twin
girls, whose DNA he had modified by using the CRISPR/Cas9 gene-editing tool.
Working with embryos, He disabled the CCR5 gene, which encodes for a
receptor that, along with another receptor, serves as a gateway for the HIV
virus to penetrate and infect white blood cells. The point of the project
was to confer a built-in genetic immunity to the virus. He said the
procedure was medically necessary given that the girls’ father is HIV-
positive.
Wang and Yang took issue with the rationale behind the project and how the
experiment was conducted. Though the full details of the work have yet to be
disclosed, the authors said the experimental design and the data presented
at the Hong Kong summit “revealed serious misconduct on both the scientific
and ethical levels.” The authors felt the need to write the commentary
article “because we believe that responsible scrutiny and discussion of
this event requires a good understanding of the scientific facts.”
The procedure was not medically necessary, they said, because an HIV
infection at the conception stage can be avoided by sticking to established
assistive reproduction protocols. As for the risk of infection after birth,
“simply avoiding potential risk of HIV exposure suffices for most people,”
the authors wrote, adding that “editing early embryos does not provide
benefits for the babies, while posing potentially serious risks on multiple
fronts.”
Those “multiple fronts” included a poor understanding of how the absence
of the CCR5 gene might affect Asian individuals, particularly the way in
which the introduced allele, or mutated gene, might cause unforeseen health
risks. This seemingly fortuitous mutation can happen naturally, and
scientists have studied the resulting effects on Europeans, who seem healthy
for the most part. That said, the CCR5 mutation does not protect
individuals from all HIV strains. What’s more, the effects of this mutation
have not been studied thoroughly in Chinese populations, therefore “it is
very difficult to predict the risk of introducing the [CCR5 allele] into a
Chinese genetic background,” the authors wrote.
“While He claimed that there was a long-term health follow-up plan, there
are no details on who will fund this or assume responsibility in the event
that any medical issues arise,” they wrote.
Wang and Yang described the quality of the science employed by He as “
substandard.” During He’s presentation in Hong Kong, for example, the
scientist said he used data about CCR5 knockout in mice in order to
determine if the deleted gene would “cause undesirable genetic,
physiological, or behavioral consequences,” as worded in He’s slide.
“This is absurd,” wrote Wang and Yang, saying it’s “not possible to
answer that question simply by comparing histology staining of four
different tissues without any quantification and by doing two simple
behavior tests in mice,” adding that the science was “very poor and
superficial.”
Other issues exposed by Wang and Yang included certain experiments that
could not be replicated, and a lack of attention paid to the potential
problems produced by off-target mutations (in which CRISPR/Cas9 might have
inadvertently altered other genes) and the potential for mosaicism (in which
an individual has acquired multiple, distinct genomes). Wang and Yang wrote
that the approach used by He was not sophisticated enough to detect any
possible off-target mutations, and that “He probably underestimated the
rate of mosaicism and the risk of introducing harmful genetic alterations.”
The authors concluded their commentary article by strongly urging the
international community of scientists and regulators to “initiate a
comprehensive discussion as soon as possible to develop the criteria and
standards for genome editing in the human germline for reproductive purposes
.” Once consensus is reached on this matter, jurisdictions can then pass
laws and build the institutions needed for oversight and enforcement, the
authors wrote.
“I agree 100% with the authors,” Brendan Parent, a bioethicist at NYU
School of Medicine, wrote in an email to Gizmodo. “He Jiankui contravened
every tenet of responsible research for the purpose of being the first to
attempt. He did not go through sufficient approval channels, his informed
consent process for the parents was misleading, and his justification was
wrong.”
Parent, who is not affiliated with the new commentary paper, said parents
with HIV can have a child unaffected by the virus through the use of in
vitro fertilization (IVF) and preimplantation genetic testing (PGT), which
involves the screening of embryos for disease prior to implantation.
“We have no clear picture what kinds of health risks these children will
experience, not knowing how genetic manipulation affects development, and
being mosaic for the CCR5 gene that was intended to be edited out—meaning
they each have partial expression for the gene,” Parent told Gizmodo. “
Furthermore, we are unaware what the mere process of germline editing does
to a human embryo brought to term, even if it was a technical success for
the intended gene edit.”
The good news about all of this is the overwhelming consensus that He did a
bad thing and that measures need to be put into place to prevent something
like this from ever happening again. Let’s hope this consensus actually
leads to action.
niuheliang (别问 |
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