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基因编辑工具CRISPR可能增加癌症风险,毕竟这不是一个奇迹

Not a Miracle Treatment after All? Gene Editing Tool CRISPR may Increase Cancer Risks

By Rhodilee Jean A. Dolor

The gene-editing tool CRISPR comes with so much potential that American scientist Jennifer Doudna and French scientist Emmanuelle Charpentier won the 2020 Nobel Prize in chemistry for its discovery.

基因编辑工具CRISPR具有巨大的潜力,美国科学家詹妮弗·杜德纳和法国科学家埃曼纽尔·夏彭蒂尔因其发现而获得2020年诺贝尔化学奖

The technology, which snips and modifies genetic material in cells, is heralded as a breakthrough that can potentially bring to life extinct species. More importantly, it offers hope of treating a slew of diseases, including blood disorders and cancer and to date, the developments in CRISPR-based therapies are promising.

这项技术可以剪断和修饰细胞中的遗传物质,被认为是一项突破,有可能使灭绝物种复活。更重要的是,它为治疗包括血液疾病和癌症在内的一系列疾病带来了希望,迄今为止,基于CRISPR的疗法的发展前景看好。

The Promising Gene Editing Technology

有前途的基因编辑技术

Last year, the US Food and Drug Administration green-lighted the clinical trial for a CRISPR-based therapy for  sickle cell disease, an inherited red blood cell disorder that afflicts millions, including 100,000 in the United States.

去年,美国食品和药物管理局(FDA)批准了一项基于CRISPR的镰状细胞病(一种遗传性红细胞疾病)治疗的临床试验,该疾病困扰着数百万人,其中包括美国的10万人。

The treatment called “exa-cel” for exagamglogene autotemcel aims to correct mutations in the beta-globin gene responsible for illness.

Exa-Cel治疗exa-Gamglogene autotemcel的目的是纠正导致疾病的β珠蛋白基因突变。

Following the results of the trial, rare disease specialist specialist Vertex and CRISPR Therapeutics, which developed treatment, revealed plans to submit exa-cel for review and approval by health regulators in the U.S., U.K., and Europe by the end  2022, which means that the treatment could potentially get marketing authorization by 2023.

根据试验结果,开发治疗的罕见疾病专家Vertex和CRISPR Therapeutics透露,计划在2022年底前将ExaCel提交给美国、英国和欧洲的卫生监管机构审查和批准,这意味着该治疗可能在2023年前获得上市许可。

CRISPR is also considered as a viable solution for global health security threats. In a review published in Pathogens and Global Health on Feb. 16, Kyle E. Watters, from the University of California Berkeley, and colleagues wrote that gene editing technologies such as CRISPR can be used to develop tools that can characterize, diagnose and treat new and existing pathogens.

CRISPR也被认为是应对全球健康安全威胁的可行解决方案。加州大学伯克利分校的凯尔·E·沃特斯及其同事在2月16日发表在《病原体与全球健康》杂志上的一篇综述中写道,CRISPR等基因编辑技术可用于开发新的和现有病原体的特征、诊断和治疗工具。

“CRISPR-based treatments that directly target a pathogen or host-cell receptors are also a promising alternative to small molecule drugs or vaccines. CRISPR is also making it possible for scientists to conduct larger, faster, and more comprehensive experiments designed to better understand the key features of pathogens.”

“直接针对病原体或宿主细胞受体的基于CRISPR的治疗也是小分子药物或疫苗的有希望的替代品。CRISPR还使科学家能够进行更大、更快和更全面的实验,以更好地了解病原体的关键特征。”

Misuse Poses Dangerous Consequences

滥用会造成危险后果

Watters and colleagues, however, acknowledged that the use of gene-editing tools comes with risks.  The researchers said that with CRISPR’s ability to delete, suppress, or amplify the expression of specific genes, intentional, reckless or accidental misuse of the technology poses dangerous risks.

然而,沃特斯及其同事承认,使用基因编辑工具有风险。研究人员表示,由于CRISPR能够删除、抑制或放大特定基因的表达,有意、鲁莽或意外滥用该技术会带来危险。

“[Genome-editing tools] could be used to disrupt the normal functioning of specific physiological systems, preferentially target specific target populations with rare genetic mutations, or hijack the human microbiome to produce harmful biochemicals or manipulate the production of natural compounds. There is also the risk that genome editing could be used to create gene drives that could spread deleterious genes through animal or plant populations.”

“[基因组编辑工具]可用于破坏特定生理系统的正常功能,优先针对具有罕见基因突变的特定目标群体,或劫持人类微生物组以产生有害生物化学物质或操纵天然化合物的生产。还有一种风险是,基因组编辑可能被用来创造基因驱动力,从而通过动物或植物种群传播有害基因。”

Safety and Feasibility 

安全性和可行性

In a study published in the journal Science in February 2020, researchers from the University of Pennsylvania used CRISPR to engineer T-cells, a type of white blood cells that play a crucial role in the body’s immune system.

在2020年2月发表在《科学》杂志上的一项研究中,宾夕法尼亚大学的研究人员使用CRISPR来设计T细胞,这是一种在人体免疫系统中发挥关键作用的白细胞。

Researcher Edward Stadtmauer, from the Abramson Cancer Center (ACC) of the University of Pennsylvania, and colleagues saw promising results in the clinical trial as the engineered cells that were administered to cancer patients were well tolerated.

宾夕法尼亚大学阿布拉姆森癌症中心(ACC)的研究人员爱德华·施塔特莫尔和他的同事在临床试验中看到了有希望的结果,因为给癌症患者使用的工程细胞具有良好的耐受性。

“Preliminary results from this pilot trial demonstrate that multiplex human genome engineering is safe and feasible using CRISPR-Cas9. The extended persistence of the engineered T cells indicates that preexisting immune responses to Cas9 do not appear to present a barrier to the implementation of this promising technology.”

“这项试点试验的初步结果表明,使用CRISPR-Cas9进行多重人类基因组工程是安全可行的。工程化T细胞的持久性表明,对Cas9的预先存在的免疫反应似乎不会阻碍这项有前景的技术的实施。”

Genomes Damaged by CRISPR may Increase Cancer Risks

CRISPR损伤的基因组可能增加癌症风险

Findings of a new study, however, suggests that the use of CRISPR comes with risks. In the new research published in the journal Nature Biotechnology on June 22, researchers from the Tel Aviv University in Israel found evidence suggesting that CRISPR therapy can damage the genome.

然而,一项新的研究结果表明,使用CRISPR有风险。在6月22日发表在《自然生物技术》杂志上的一项新研究中,以色列特拉维夫大学的研究人员发现了表明CRISPR疗法可能损害基因组的证据。

Adi Barzel, from the university’s School of Neurobiology, Biochemistry and Biophysics, and colleagues wanted to assess the risk-benefit ratio of using CRISPR if the broken DNA from CRISPR treatment does not recover so they replicated the experiment of the researchers from the University of Pennsylvania.

该大学神经生物学、生物化学和生物物理学学院的阿迪·巴泽尔及其同事希望评估如果CRISPR治疗中的断裂DNA无法恢复,使用CRISPR的风险效益比,因此他们复制了宾夕法尼亚大学研究人员的实验。

The group cleaved the T-cells genome in the exact location and used a method known as single-cell RNA sequencing to examine individual cells.

该小组在准确的位置切割T细胞基因组,并使用单细胞RNA测序方法来检测单个细胞。

They found that there was significant loss of genetic material in some of the cells. After chromosome 14 was cleaved, for instance, about 5% of the cells exhibit little or no expression of this chromosome. The damage is worse when cleaving was done simultaneously. The researchers found that 9%, 10%, and 3% of the cells were unable to repair the damage in chromosomes 14, 7, and 2, respectively.

他们发现一些细胞中的遗传物质有明显的损失。例如,在染色体14被切割后,约5%的细胞表现出很少或没有该染色体的表达。同时进行切割时,损伤更严重。研究人员发现,分别有9%、10%和3%的细胞无法修复染色体14、7和2的损伤。

Barzel warned that the extent of loss in genetic material potentially increases risk for cancer.

巴泽尔警告说,遗传物质丢失的程度可能会增加患癌症的风险。

“We found that the cause for the difference in damage was the exact place of the cleaving on each of the three chromosomes. Altogether, our findings indicate that over 9% of the T-cells genetically edited with the CRISPR technique had lost a significant amount of genetic material. Such loss can lead to destabilization of the genome, which might promote cancer.”

“我们发现,造成损伤差异的原因是三条染色体上每一条染色体的确切切割位置。总之,我们的发现表明,使用CRISPR技术进行基因编辑的T细胞中有超过9%丢失了大量遗传物质。这种丢失可能导致基因组不稳定,从而可能促进癌症。”

Based on the results, the researchers said that extra caution should be taken when using CRISPR therapy.

基于这些结果,研究人员表示,在使用CRISPR治疗时应格外小心。

“At 11 days after transfection, 0.9% of T cells still had a chromosome 14 loss. Aneuploidy and chromosomal truncations are, thus, frequent outcomes of CRISPR–Cas9 cleavage that should be monitored and minimized in clinical protocols.”

“在11点 转染后几天,0.9%的T细胞仍有14号染色体丢失。因此,非整倍体和染色体截断是CRISPR–Cas9切割的常见结果,应在临床方案中进行监测和最小化。”

Barzel and colleagues also recommended further study into two alternative solutions that can potentially address the problem: one is to reduce the production of damaged cells and the second is to identify and remove damaged cells before the engineered materials are administered to the patient.

Barzel及其同事还建议进一步研究两种可能解决该问题的替代方案:一种是减少受损细胞的产生,另一种是在向患者施用工程材料之前识别并移除受损细胞。

Risks and Benefits

风险以及带来的好处

The researchers said that they are aware of the substantial advantages offered by CRISPR but the study is intended to shed light on the potential risks of the  technology.

研究人员表示,他们意识到CRISPR提供的实质性优势,但这项研究旨在阐明该技术的潜在风险。

“We advance this highly effective technology, while at the same time cautioning against its potential dangers. This may seem like a contradiction, but as scientists we are quite proud of our approach, because we believe that this is the very essence of science: we don’t ‘choose sides.’ We examine all aspects of an issue, both positive and negative, and look for answers.”

“我们在推进这项高效技术的同时,也对其潜在的危险提出了警告。这似乎是一个矛盾,但作为科学家,我们对我们的方法感到非常自豪,因为我们相信这是科学的本质:我们不‘选边站’。我们研究问题的所有方面,包括正面和负面,并寻找答案。”

图片出处

STARSET_Mirror

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