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美国正着手加强对可能使病毒变得更危险的研究的监督。

The United States is moving to tighten oversight of studies that could make viruses more dangerous.

In a U.S. government lab in Bethesda, Maryland, virologists plan to equip the strain of the monkeypox virus that spread globally this year, causing mostly rash and flulike symptoms, with genes from a second monkeypox strain that causes more serious illness. Then they’ll see whether any of the changes make the virus more lethal to mice. The researchers hope that unraveling how specific genes make monkeypox more deadly will lead to better drugs and vaccines.

在马里兰州贝塞斯达市的一个美国政府实验室里,病毒学家计划将今年在全球传播的猴痘病毒的品系与引发更严重疾病的第二种猴痘病毒品系的基因结合起来。这种病毒主要引起皮疹和类似流感的症状。然后他们将观察这些变化是否会使病毒对老鼠的杀伤力更大。研究人员希望,揭示特定基因如何使猴痘更致命,将有助于研制出更好的药物和疫苗。

Some scientists are alarmed by the planned experiments, which were first reported by Science. If a more potent version of the outbreak strain accidentally escaped the high-containment, high-security lab at the National Institute of Allergy and Infectious Diseases (NIAID), it could spark an “epidemic with substantially more lethality,” fears epidemiologist Thomas Inglesby, director of the Center for Health Security at the Johns Hopkins University Bloomberg School of Public Health. That’s why he and others argue the experiments should undergo a special review required for especially risky U.S.-funded studies that might create a pathogen that could launch a catastrophic pandemic.

《科学》杂志首先报道了这些计划中的实验,一些科学家对此感到震惊。约翰霍普金斯大学布隆伯格公共卫生学院卫生安全中心主任、流行病学家Thomas Inglesby担心,如果一种更强的爆发菌株意外地从国家过敏和传染病研究所(NIAID)的高控制、高安全的实验室逃脱,它可能引发一场“杀伤力大得多的流行病”。这就是为什么他和其他人认为,这些实验应该经过特别的审查,这是美国资助的特别有风险的研究所需要的,这些研究可能会产生一种病原体,引发灾难性的流行病。

But it’s not clear that the rules apply to the proposed study. In a 2018, a safety panel determined it was exempt from review. Monkeypox did not meet the definition of a “potential pandemic pathogen” (PPP), the panel decided, because it didn’t spread easily. Now, with monkeypox widespread, the National Institutes of Health (NIH) is planning to reexamine the work, but it still might not qualify as “enhancing” a PPP, the agency says. That’s because the study will swap natural mutations, not create new ones, so it is not expected to create a monkeypox strain more virulent than the two already known.

但尚不清楚这些规则是否适用于拟议中的研究。在2018年的一次审查中,一个安全小组决定该公司免于审查。专家组认为,猴痘不符合“潜在大流行病原体”(PPP)的定义,因为它不容易传播。现在,随着猴痘的广泛传播,美国国家卫生研究院(NIH)正计划重新检查这项工作,但该机构表示,它仍可能不符合“增强”PPP的资格。这是因为这项研究将交换自然突变,而不是创造新的突变,因此预计不会创造出比已知的两种更致命的猴痘菌株。

The monkeypox controversy marks just the latest flare-up in a decade-old debate over exactly when a study that alters a pathogen is too risky for the U.S. government to fund—and who should have the power to decide. That wrangling became especially ferocious over the past 2 years, as the COVID-19 pandemic spawned allegations, so far unproven, that SARS-CoV-2 escaped from a laboratory in China. Now, in the pandemic’s wake, the U.S. government appears poised to make sizable changes to how it manages so-called gain-of-function (GOF) studies that tweak pathogens in ways that could make them spread faster or more dangerous to people.

关于一项改变病原体的研究在什么时候对美国政府来说风险太大而无法资助的争论已经持续了十年,而猴痘的争议标志着这场争论的最新爆发——谁应该有权做出决定。在过去两年里,这种争论变得尤为激烈,因为COVID-19大流行引发了迄今尚未得到证实的指控,即SARS-CoV-2从中国的一个实验室泄漏出去。现在,在大流行之后,美国政府似乎准备在管理所谓的“功能获得”(GOF)研究方面做出相当大的改变,这种研究调整病原体的方式,可能使它们对人类传播得更快或更危险。

Last month, an expert panel convened by NIH and its parent agency, the Department of Health and Human Services (HHS), released a draft report that recommends the GOF rules be broadened to include pathogens and experiments that are exempt from the current scheme. If the recommendation is adopted—which could come next year—the monkeypox study could come under tighter scrutiny. And other researchers working with viruses such as Ebola, seasonal flu strains, measles, and even common cold viruses could face new oversight and restrictions.

上个月,由NIH及其下属机构——美国卫生与公众服务部(HHS)召集的一个专家小组发布了一份报告草案,建议将GOF规则扩大到包括不受当前计划限制的病原体和实验。如果该建议被采纳(可能在明年),猴痘研究将受到更严格的审查。其他研究埃博拉病毒、季节性流感病毒、麻疹甚至普通感冒病毒的研究人员可能面临新的监管和限制。

Some scientists are watching nervously, worried that an expanded definition could worsen what they already see as a murky, problematic oversight system. The existing rules, they say, have caused confusion and delays that have deterred scientists from pursuing studies critical to understanding emerging pathogens and finding ways to fight them. If not implemented carefully, the proposed changes could “greatly impede research into evolving or emerging viruses,” worries virologist Linda Saif of Ohio State University, Wooster. She and others say expanding the regulations could add costly red tape, potentially driving research overseas or into the private sector, where U.S. regulations don’t apply or are looser.

一些科学家正紧张地关注着,他们担心扩大定义可能会使他们已经认为模糊、有问题的监管体系恶化。他们说,现有的规则造成了混乱和拖延,阻碍了科学家进行对了解新出现的病原体和找到对抗它们的方法至关重要的研究。俄亥俄州立大学伍斯特分校的病毒学家琳达·赛义夫担心,如果不仔细实施,提出的改变可能会“极大地阻碍对进化或新兴病毒的研究”。她和其他一些人说,扩大监管可能会增加成本高昂的繁文缛节,可能会推动研究转向海外或私营部门,这些领域不适用美国的监管规定,或更宽松。

Others say the proposed changes don’t go far enough. They’d like to see the U.S. government create an entirely new independent body to oversee risky research, and for the public to get far more information about proposed experiments that could have fearsome consequences. Some have even called for curbing the now common practice of collecting viruses from wild animals and studying them in the lab, saying it only increases the risks that the viruses—or modified versions—will jump to humans.

其他人则表示,提议的改革还不够深入。他们希望看到美国政府建立一个全新的独立机构来监督有风险的研究,并让公众获得更多有关可能产生可怕后果的拟议实验的信息。一些人甚至呼吁遏制从野生动物身上收集病毒并在实验室进行研究的普遍做法,称这只会增加病毒——或改良版本——传染给人类的风险。

“We really should be asking important questions about whether that work should continue,” Inglesby says. And virologist James LeDuc, who retired last year as director of the University of Texas Medical Branch’s Galveston National Laboratory, says, “It’s one thing to recognize that these viruses exist in nature. It’s another to modify them so that you can study them if in fact they could become human pathogens.”

“我们真的应该问一些重要的问题,关于这项工作是否应该继续,”Inglesby说。病毒学家James LeDuc去年从德克萨斯大学医学分支加尔维斯顿国家实验室主任的职位上退休,他说:“认识到这些病毒存在于自然界是一回事。如果它们实际上可能成为人类病原体,那么修改它们以便研究它们就是另一回事了。”

All sides agree on one thing: The proposed rules represent a potential pivot point in the debate over the funding of high-risk GOF studies by the U.S. government, which is one of the world’s largest supporters of virology research. “There are significant potential risks to both under- and overregulation in this field,” says virologist Jesse Bloom of the Fred Hutchinson Cancer Center, who like LeDuc is part of a group of scientists pushing for the changes. “The goal,” he adds, “needs to be to find the right balance.”

各方都同意一件事:拟议的规则代表了有关美国政府为高风险GOF研究提供资金的辩论的潜在支点,美国政府是世界上病毒学研究的最大支持者之一。弗雷德·哈钦森癌症中心的病毒学家杰西·布鲁姆说:“在这个领域,监管不足和过度都有重大的潜在风险。”他和勒杜克一样,都是推动这些变革的科学家团体的一员。“目标,”他补充道,“需要找到正确的平衡。”

THE CONTROVERSY over studies that enhance or alter pathogens ignited a decade ago, but such work goes back more than a century. To make vaccines, for example, virologists have long passaged, or repeatedly transferred, a virus between dishes of animal cells or whole animals, so that it loses its ability to harm people but grows better—a gain of function. Since the late 1990s, genetic engineering techniques have made these studies much more efficient by allowing virologists to assemble new viral strains from genomic sequences and to add specific mutations.

关于增强或改变病原体研究的争议在十年前就已经引发,但这类工作可以追溯到一个多世纪以前。例如,为了制造疫苗,病毒学家在动物细胞或整个动物的培养皿之间长期传代或反复转移病毒,这样病毒就失去了伤害人类的能力,但生长得更好——获得了功能。自20世纪90年代末以来,基因工程技术使这些研究变得更加有效,病毒学家可以从基因组序列中组装新的病毒株,并添加特定的突变。

In 2011, two such NIH-funded experiments with H5N1 avian influenza set off alarm bells worldwide. Virologists Yoshihiro Kawaoka at the University of Wisconsin, Madison, and the University of Tokyo and Ronald Fouchier at Erasmus University Medical Center were interested in identifying mutations that could enable the virus, which normally infects birds, to also spread easily among mammals, including humans. Small but frightening outbreaks had shown H5N1 could spread from birds to people, killing 60% of those infected. By introducing mutations and passaging, Kawaoka and Fouchier managed to tweak the virus so it could spread between laboratory ferrets, a stand-in for humans.

2011年,美国国家卫生研究院资助的两项H5N1禽流感实验在全世界敲响了警钟。威斯康星大学麦迪逊分校的病毒学家Yoshihiro Kawaoka、东京大学的病毒学家以及伊拉斯谟大学医学中心的Ronald Fouchier都对识别病毒突变感兴趣,这些突变可能使这种通常感染鸟类的病毒也容易在包括人类在内的哺乳动物中传播。小型但可怕的疫情表明H5N1病毒可以从鸟类传播给人类,60%的感染者死亡。通过引入突变和传代,Kawaoka和Fouchier成功地调整了病毒,使其可以在实验室雪貂(人类的替身)之间传播。

Controversy erupted after Fouchier discussed the work at a scientific meeting prior to publication. Soon, worries that the information could land in the wrong hands or that the tweaked virus could escape the lab prompted journal editors and government officials to call for a review by an HHS panel called the National Science Advisory Board for Biosecurity (NSABB). HHS established NSABB after the 2001 anthrax attacks in the United States to consider so-called dual use research that could be used for both good and ill. During the review, flu researchers worldwide voluntarily halted their GOF experiments. Ultimately, NSABB concluded the scientific benefits of the studies outweighed the risks; the H5N1 papers were published and the work resumed.

Fouchier在发表之前的一次科学会议上讨论了这项工作,引发了争议。很快,由于担心这些信息可能会落入坏人之手,或者调整后的病毒可能会逃离实验室,期刊编辑和政府官员呼吁卫生与公众服务部一个名为国家生物安全科学顾问委员会(NSABB)的小组进行审查。在2001年美国发生炭疽热袭击后,卫生与公众服务部成立了NSABB,以考虑所谓的双重用途研究,这种研究可以用于好的方面,也可以用于坏的方面。在审查期间,全球流感研究人员自愿停止了他们的GOF实验。最终,NSABB得出结论,研究的科学益处超过了风险;H5N1的论文发表了,研究工作继续进行。

Then in mid-2014, several accidents at U.S. labs working with pathogens, along with worries about some new GOF papers, prompted the White House to impose a second “pause” on U.S.-funded GOF research. It halted certain studies with influenza and the coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS), SARS-CoV-2 cousins that have caused small though deadly outbreaks. NIH ultimately identified 29 potential GOF projects in its funding portfolio. After reviews, the agency allowed 18 to resume because it determined they didn’t meet the risky GOF definition or were urgent to protect public health. Some, for example, adapted MERS to infect mice, a step that can help researchers develop treatments. The remaining 11 studies had GOF components that were removed or put on hold.

然后在2014年年中,美国实验室研究病原体的几起事故,以及对一些新的GOF论文的担忧,促使白宫对美国资助的GOF研究实施了第二次“暂停”。它停止了对流感和导致中东呼吸综合征(MERS)和严重急性呼吸综合征(SARS)的冠状病毒的某些研究,这些冠状病毒是SARS- cov -2的表亲,曾造成小规模但致命的疫情。NIH最终在其资助组合中确定了29个潜在的GOF项目。经过审查,该机构批准了18个项目的恢复,因为它确定这些项目不符合危险的GOF定义,或者对保护公众健康至关重要。例如,有些病毒改造了中东呼吸综合征来感染老鼠,这一步骤可以帮助研究人员开发治疗方法。其余11项研究的GOF成分被移除或搁置。

DURING THE SECOND PAUSE, U.S. officials promised to come up with a more comprehensive approach to identifying and potentially blocking risky studies before they began. Advocates of tighter rules also pushed for less-risky approaches for studying altered viruses, such as using weakened virus strains, computer models, or “pseudoviruses” that can’t replicate.

在第二次暂停期间,美国官员承诺提出一种更全面的方法,在有风险的研究开始前就识别并可能阻止它们。更严格规则的倡导者还推动采用风险更低的方法来研究变异病毒,例如使用减弱的病毒株、计算机模型或无法复制的“假病毒”。

Many virologists, however, argued that only studies with live virus can accurately show the effect of a mutation. “There’s only so much you can learn [from alternative techniques],” says University of Michigan, Ann Arbor, virologist Michael Imperiale, who supported the H5N1 GOF studies. “Sometimes using intact virus is the best approach.”

然而,许多病毒学家认为,只有用活病毒进行的研究才能准确地显示突变的影响。支持H5N1 GOF研究的密歇根大学安娜堡分校病毒学家Michael Imperiale说:“(从替代技术中)你只能学到这么多。”“有时使用完整的病毒是最好的方法。”

In 2017, the debate culminated with the release of the current HHS policy, dubbed Potential Pandemic Pathogen Care and Oversight (P3CO). It requires that an HHS panel review any NIH-funded study “reasonably anticipated” to generate an enhanced version of a pathogen that is highly virulent, highly transmissible, and might cause a pandemic. But it exempts natural, unmodified viruses and GOF work done to develop vaccines or as part of surveillance efforts, such as tweaking a circulating flu virus to assess the risks of a newly observed variant.

2017年,这场辩论随着当前HHS政策的发布而达到高潮,该政策被称为潜在大流行病原体护理和监管(P3CO)。它要求卫生与公众服务部的一个小组审查任何nih资助的“合理预期”产生高毒性、高传染性、可能导致大流行的增强版病原体的研究。但它免除了天然的、未修饰的病毒和为开发疫苗或作为监测工作一部分而进行的GOF工作,如调整一种流通的流感病毒以评估新观察到的变体的风险。

The HHS committee charged with implementing the policy, which operates behind closed doors, has since reviewed only three projects, and approved all. Two were continuations of Kawaoka’s and Fouchier’s H5N1 work. (Both grants are now expired.) The third involved work with H7N9 avian influenza, but the investigator later agreed to use a nonpathogenic flu strain.

负责实施该政策的美国卫生与公众服务部委员会是秘密运作的,自那以后只审查了三个项目,并批准了所有项目。其中两项是Kawaoka和Fouchier的H5N1研究的延续。(两项拨款现已过期。)第三项研究涉及H7N9禽流感,但研究人员后来同意使用一种非致病性流感毒株。

Other concerning studies have been given a pass, critics say. As an example, they point to work led by coronavirus expert Ralph Baric of the University of North Carolina, Chapel Hill. In the 2000s, his team became interested in determining whether bat coronaviruses had the potential to infect humans. (COVID-19 has since shown the answer is emphatically yes.) But the researchers often could not grow the viruses in the laboratory or enable them to infect mice. So they created hybrid, or chimeric, viruses, grafting the gene encoding the surface protein, or “spike,” that the wild bat virus uses to enter a host cell into a SARS strain that infects mice.

批评人士说,其他相关研究都被放行了。他们以北卡罗来纳大学教堂山分校的冠状病毒专家拉尔夫·巴里克领导的研究为例。在21世纪初,他的团队开始对确定蝙蝠冠状病毒是否有可能感染人类感兴趣。(自2019冠状病毒病以来,答案显然是肯定的。)但研究人员通常无法在实验室中培养病毒或使其感染小鼠。因此,他们创造了杂交或嵌合病毒,将野生蝙蝠病毒用来进入宿主细胞的表面蛋白或“刺突”基因嫁接到感染老鼠的SARS毒株中。

NIH let this work continue during the 2014 pause. The researchers had no intention of making the mouse-adapted SARS virus more risky to people, Baric has said. But something unexpected happened when his lab added spike from a bat coronavirus called SHC014: The chimeric virus sickened mice carrying a human lung cell receptor, Baric’s team reported in 2015 in Nature Medicine. The hybrid virus could not be stopped by existing SARS antibodies or vaccines. In essence, critics of the work assert, it created a potential pandemic pathogen.

在2014年暂停期间,NIH让这项工作继续进行。Baric说,研究人员无意让适应老鼠的SARS病毒对人类的风险更大。但当他的实验室添加了一种名为SHC014的蝙蝠冠状病毒的尖刺时,意想不到的事情发生了:这种嵌合病毒使携带人类肺细胞受体的老鼠患病,巴里克的团队在2015年的《自然医学》(Nature Medicine)上报道。现有的SARS抗体或疫苗无法阻止这种混合病毒。这项工作的批评者断言,从本质上说,它创造了一种潜在的大流行病原体

A review panel might “deem similar studies building chimeric viruses based on circulating [bat coronavirus] strains too risky to pursue,” Baric acknowledged. Yet he has also called these chimeric viruses “absolutely essential” to efforts to test antiviral drugs and vaccines against coronaviruses, and many virologists agree. They also argue that Baric’s work and related experiments provided an early warning that, if heeded, might have helped the world prepare for the COVID-19 pandemic.

Baric承认,一个审查小组可能“认为基于循环的(蝙蝠冠状病毒)菌株构建嵌合病毒的类似研究风险太大,无法进行”。然而,他也称这些嵌合病毒对测试对抗冠状病毒的抗病毒药物和疫苗的努力是“绝对必要的”,许多病毒学家同意这一点。他们还认为,Baric的工作和相关实验提供了早期预警,如果得到重视,可能会帮助世界为COVID-19大流行做好准备。

THE PANDEMIC HAS SUPERCHARGED the GOF debate, in large part because of unproven but high-profile allegations—including from former President Donald Trump—that SARS-CoV-2 emerged from a laboratory in Wuhan, China. One prominent advocate of the lab-leak theory, Senator Rand Paul (R–KY), a senior member of the Senate’s health panel, has sparred with NIAID Director Anthony Fauci over experiments in virologist Shi Zhengli’s lab at the Wuhan Institute of Virology (WIV). With money from an NIH grant to a U.S. nonprofit organization, the EcoHealth Alliance, Shi had created chimeras by adding spike proteins from wild bat coronaviruses to a SARS-related bat strain called WIV1. The WIV researchers used methods developed by Baric, who has collaborated with Shi.

大流行加剧了GOF的辩论,这在很大程度上是因为未经证实但备受关注的指控——包括前总统唐纳德·特朗普——称SARS-CoV-2来自中国武汉的一个实验室。实验室泄漏理论的一个著名倡导者,参议员兰德·保罗(R-KY),参议院卫生小组的资深成员,与美国国家传染病研究所主任安东尼·福奇就武汉病毒学研究所病毒学家施正立实验室的实验发生了争执。利用NIH向美国非营利组织生态健康联盟(EcoHealth Alliance)提供的资金,施通过将野生蝙蝠冠状病毒的刺突蛋白添加到一种名为WIV1的与SARS相关的蝙蝠毒株中,创造了嵌合体。WIV的研究人员使用了Baric开发的方法,他与施合作过。

Last year, documents obtained by the Intercept showed that—like Baric’s work during the 2014 pause—NIH had exempted the EcoHealth grant from the P3CO policy. (The agency later explained that the bat coronaviruses were not known to infect humans.) But NIH also said that if Shi’s lab observed a 10-fold increase in a chimeric virus’ growth compared with WIV1, it wanted to be informed, because the experiments could then require a P3CO review.

去年,Intercept获得的文件显示,与Baric在2014年暂停期间的工作一样,NIH已将生态健康拨款从P3CO政策中豁免。(该机构后来解释说,还不知道蝙蝠冠状病毒会感染人类。)但NIH也表示,如果Shi的实验室观察到嵌合病毒的生长速度比WIV1增长了10倍,它希望得到通知,因为实验可能需要P3CO审查。

The documents show WIV did observe increased growth in the lungs of infected mice and more weight loss and death in some animals. NIH has said EcoHealth failed to report these “unexpected” results promptly as required, but EcoHealth disputes this. Paul and some proponents of the lab-leak theory have gone further, alleging that NIH actively conspired with EcoHealth to hide the risks of the study.

这些文件显示,WIV确实观察到受感染小鼠的肺部生长增加,一些动物的体重减轻和死亡更多。NIH表示,生态健康公司未能按要求及时报告这些“意外”结果,但生态健康公司对此表示异议。保罗和一些实验室泄漏理论的支持者走得更远,声称NIH积极地与生态健康公司合谋,隐瞒了这项研究的风险。

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