美国情报部门现在承认，冠状病毒大流行可能是武汉病毒学研究所内部有争议的实验的结果。2017年2月23日，中国病毒学家史在武汉实验室内。-

就在美国超过中国成为Covid-19病例最多的国家后一天，美国国防情报局更新了对这种新型冠状病毒来源的评估，以反映它可能是从传染病实验室意外释放的。新闻周刊已经学会了。

这份日期为3月27日、并得到两名美国官员证实的报告显示，美国情报部门修改了其1月份的评估，其中“判断疫情可能是自然发生的”，现在包括了新冠状病毒“意外”出现的可能性，原因是中国中部城市武汉的“不安全实验室实践”，去年年底首次在武汉发现了该病原体。这份名为“中国:COVID-19爆发的起源仍然未知”的分类报告排除了这种疾病是作为生物武器被基因工程改造或故意释放的可能性。

“我们没有可信的证据表明非典-CoV-2是故意释放的或者是作为生物武器制造的，”报告发现。“在没有已知有效疫苗的情况下，研究人员或中国政府不太可能故意释放如此危险的病毒，尤其是在中国境内。”每一个被采访的科学家新闻周刊因为这个故事也断然否定了病毒是故意释放的说法。

Covid-19已经感染了全球近300万人，最初肆虐中国，之后在西方遭受重创，美国成为受影响最严重的国家，截至4月27日，已有超过55000人死亡。它的起源不仅是科学辩论的主题，也是国际社会充满政治色彩的争议。

引用学术文献，美国糖尿病学会的文件指出，对于这种疾病是如何真正首先出现的“最终答案可能永远都不知道”。美国情报发言人告诉记者新闻周刊“情报界还没有就任何一种理论达成一致。”

不确定来源

追踪新病毒的来源并不容易。武汉研究所的研究人员花了十多年的时间才把2002-2003年的非典病毒追踪到云南省偏远的蝙蝠洞。根据国防情报局的文件，毫不奇怪，在二月初，中国军事医学科学院“得出结论，他们不可能科学地确定Covid-19的爆发是自然引起的还是实验室事故意外引起的”。

中国政府进行的初步评估指出，该市的华南海产品市场很可能是导致非典(SARS)自然爆发的原因——CoV-2是一种导致Covid-19的新冠状病毒。在疫情爆发的早期，当地官员淡化了这种病毒在人与人之间传播的可能性，并让那些对日益严重的疫情直言不讳的医生闭嘴。它可能有未计算的死亡人数和Covid-19病例数。一个关于美国有意在武汉种植病毒的虚假理论也开始流传。

中国外交部4月23日告诉记者，世界卫生组织“没有发现任何证据”武汉实验室开始爆发疫情，武汉病毒研究所副所长、中国科学院武汉分院院长袁志明抨击故意误用或创造的推论是“恶意的”和“不可能的”

“美国加尔维斯顿国家实验室的主任明确表示，我们的实验室与欧洲和美国的实验室管理得一样好，”他说。“我认为人们建立这种联系是可以理解的。但这是一个恶意的举动，目的是误导人们“认为病毒是从[我们的武汉]实验室逃出来的”。

“他们没有证据或逻辑来支持他们的指控。他们完全基于自己的推测。”

然而，美国国防部的报告援引美国政府和中国研究人员的话称，他们发现“最初发现的41例病例中，约有33%没有直接接触”市场。这一点，加上过去几年实验室的工作，引起了合理的怀疑，认为这次大流行可能是由实验室的错误引起的，而不是由黑市引起的。

这是科学和间接证据显示的。

早在2002年，当非典在中国广东省出现时，它就敲响了警钟。在接下来的几十年里，美国、中国和其他国家投入大量资金，努力搜寻并记录野生动物身上的奇怪新病原体，并计算出它们对人类构成了多大的威胁，目的是防止下一次毁灭性的大流行。

2019年秋天，非典冠状病毒出现在大都市武汉的中心。中国官员起初坚持认为，只有通过与动物的直接接触才能感染非典病毒。但是武汉的许多早期病人与野生动物市场没有联系，这意味着病毒已经在人与人之间传播。当这一事实出现时，它使人们对来自中国的信息的真实性产生了怀疑，但这种病毒很可能会成为一种致命的流行病。

在早期，关于病毒起源的流行理论是，它像非典一样，在蝙蝠中出现，传给其他哺乳动物，如穿山甲，并最终通过野生动物市场进入种群。

到了三月，野生病毒理论仍然是最有可能解释非典起源的理论——CoV-2——但是它开始显得有点参差不齐。首先，离武汉市中心动物市场不远的武汉病毒学研究所收藏了世界上最大的野生蝙蝠冠状病毒，其中至少有一种病毒与非典病毒CoV-2相似。此外，武汉病毒学研究所的科学家在过去五年中一直从事所谓的“功能增益”(GOF)研究，该研究旨在增强病毒的某些特性，以预测未来的大流行。功能增益技术已经被用于将病毒转化为能够引起全球大流行的人类病原体。

这不是地下军事掩体中邪恶的秘密计划。武汉实验室获得了一项为期十年、耗资2亿美元的国际项目“预测”的资助，该项目由美国国际开发署和其他国家资助。类似的工作，部分由美国国家卫生研究院资助，已经在世界各地的几十个实验室进行。这些研究中的一些涉及到携带致命病毒并增强其在人群中快速传播的能力——这些研究是在数百名科学家的反对下进行的，这些科学家多年来一直警告该项目有可能导致大流行。

在非典爆发后的几年里，世界各地的实验室都发生了许多涉及病原体意外释放的事故。美国已经发生了数百起泄密事件，其中包括2014年美国政府实验室泄漏的炭疽，导致84人暴露。2004年，非典病毒从北京的一个实验室逃脱，导致四人感染和一人死亡。意外释放并不复杂，也不需要恶意意图。实验室工作人员只需要生病，回家过夜，然后不知不觉地将病毒传播给他人。

据报道，2018年1月19日，美国驻北京大使馆的官员在一份电报中警告说，武汉研究所有假冒行为的记录，这可能导致意外释放。据《华盛顿邮报》报道，电报称，“在与WIV实验室的科学家互动期间，他们注意到新实验室严重缺乏安全操作这个高密封实验室所需的训练有素的技术人员和调查人员。”。

可以肯定的是，没有证据表明SARS-Cov-2来自武汉实验室，也没有证据表明该病毒是工程产品。大多数科学家认为，基于现有的证据，自然起源是最有可能的解释。但是他们也没有排除这些可能性。世界卫生组织在一份声明中称:“在现阶段，不可能准确确定导致COVID-19大流行的病毒的来源。”新闻周刊。“所有可获得的证据表明，这种病毒来源于自然动物，而不是操纵或构建的病毒。”

间接证据足够有力，足以证明实验室的程序和实践是调查的核心。值得重新审视的是，科学家们在努力保护公众免受自然病原体的威胁时，是否做得过火了。

动物传代

十年前，新闻中最多的病毒病原体不是冠状病毒，而是流感——特别是一种被称为H5N1的流感，它在鸟类中出现，杀死了很大比例的感染者。病毒一度成为头条新闻。后来很明显，几乎所有感染禽流感病毒的人都是通过接触鸟类直接感染的。要引起瘟疫，仅仅病毒是一个有效的杀手是不够的。它还必须能很容易地从一个人传给另一个人，这种品质叫做遗传性。

大约在这个时候，荷兰伊拉斯谟大学的科学家罗恩·福切尔想知道禽流感病毒变异成鼠疫病毒需要什么条件。这个问题对于病毒学家预测人类大流行的任务很重要。如果H5N1病毒离获得人类传播能力只有一两步之遥，那么世界就处于危险之中:一种可传播的H5N1病毒可能会迅速发展成一场毁灭性的大流行，其规模相当于1918年导致数千万人死亡的流感。

为了回答这个问题，科学家必须在实验室的细胞培养中培育这种病毒，并观察它是如何变异的。但是这种工作很难实施，也很难从中得出结论。你怎么知道最终结果是否可以传播？

福克尔想出的答案是一种被称为“动物通道”的技术，在这种技术中，他通过将禽流感病毒传递给动物而不是细胞培养物来使其变异。他选择雪貂是因为它们被广泛认为是人类的好替身——如果一种病毒能在雪貂之间跳跃，它也有可能在人类之间跳跃。他会用禽流感病毒感染一只雪貂，等到它生病，然后用棉签取出在雪貂体内复制的病毒样本。当病毒在体内繁殖时，它会轻微变异，所以从雪貂体内出来的病毒与进入体内的病毒略有不同。然后，富歇尔开始玩一个版本的电话:他会从第一只雪貂身上提取病毒并感染第二只，然后从第二只雪貂身上提取突变病毒并感染第三只，依此类推。

在将病毒传给10只雪貂后，富歇尔注意到相邻笼子里的一只雪貂生病了，尽管这两只雪貂彼此没有接触过。这表明这种病毒可以在雪貂中传播，也可以在人类中传播。Fouchier在他的实验室里成功地制造了一种潜在的大流行病毒。

当富歇尔向杂志提交他的动物通道工作时科学2011年，奥巴马政府的生物安全官员担心这种危险的病原体可能会意外地从富歇尔的实验室中泄漏出来，他们敦促暂停这项研究。福奇尔在BSL-2实验室完成了他的工作，该实验室针对的是中等严重度的病原体，如葡萄球菌，而不是针对埃博拉和类似病毒的BSL-4。BSL-4实验室有复杂的安全措施——它们通常是独立的建筑，有自己的空气循环系统、气闸等等。作为回应，国家卫生研究院发布了一项暂停研究的声明。

随后，科学家们就功能增益研究的风险与收益展开了激烈的辩论。哈佛大学流行病学家马克·利普西奇在杂志上写道自然2015年，“实验室事故引发大流行，导致数百万人死亡的独特风险”

利普西奇和其他17名科学家成立了剑桥工作组进行反对。它发表声明指出，美国涉及天花、炭疽和禽流感的实验室事故“一直在加速，平均每周发生两次以上”

“实验室创造高传染性的新型危险病毒株...会带来更大的风险。“在这种情况下，意外感染可能引发难以控制或不可能控制的疫情。从历史上看，新的流感毒株一旦在人群中传播，就会在两年内感染世界人口的四分之一或更多。”200多名科学家最终认可了这一立场。

功能增益研究的支持者也同样充满热情。“我们需要GOF的实验，”福切尔在1999年写道自然，以证明基因或突变与病原体的特定生物特征之间的因果关系。GOF方法在传染病研究中是绝对必要的。”

国家卫生研究院最终站在了富基尔和其他支持者的一边。它认为功能增益研究值得冒这样的风险，因为它让科学家们能够制备抗病毒药物，在大流行发生时可能有用。

到2017年国家卫生研究院解除禁令时，已经批准了几十个例外。始于2009年的“预测”项目在10年内花费了2亿美元，让世界各地的病毒学家寻找新病毒，并对它们进行功能增益研究。该项目的资金在2018年用完，没有更新。今年早些时候，在特朗普政府因取消该计划而招致批评后，它批准了一项6个月的延期。

当当前的流行病来袭时，动物通道实验已经变得司空见惯。世界上30多个BSL-4实验室中的许多实验室的科学家已经使用它们来提高呼吸道病原体的传播能力。

这项工作在当前的大流行期间有帮助吗？在最近的一篇文章中柳叶刀乔治城大学新兴传染病专家科林·卡尔森认为，由预测公司资助的工作有助于病毒学家在SARS-CoV-2病毒出现后迅速对其进行分离和分类。然而，这项研究“本可以更好地定位整体影响”尽管该项目发现了数百种新病毒，但科学家几乎不可能评估它们对人类的风险。唯一的辨别方法是“观察人类感染”

罗格斯大学的传染病专家理查德·埃布莱特说得更直白。“预测项目没有产生任何有助于预防或抗击疾病爆发的结果——绝对没有。该项目中没有任何信息会以任何方式、形式或形式有助于应对即将爆发的疫情。这项研究没有提供对开发抗病毒药物有用的信息。它没有提供对开发疫苗有用的信息。”

离武汉市中心动物市场不远的武汉病毒学研究所收藏了世界上最大的野生蝙蝠冠状病毒。该实验室是世界上获准处理4类病原体(P4)的少数实验室之一，这种危险的病毒具有很高的人际传播风险。

中国的角色

武汉病毒学研究所是众多获得预测资助的实验室之一。病毒学家-李(音)因其团队在收集数百种冠状病毒方面的工作而被称为“蝙蝠女”(bat woman)，她和她在研究所的工作人员探索了被认为在2002年引发了最初的非典病毒的蝙蝠洞穴。她的科学家们深入偏远的洞穴，擦拭蝙蝠的肛门并收集它们的排泄物。当他们回到实验室时，他们培养他们发现的病毒，确定它们的基因组序列，并试图确定它们如何感染实验室中的细胞和动物。

该研究所在2015年开始了一项针对蝙蝠冠状病毒的功能增益研究项目。这包括选择病毒株，并试图提高这些病毒在人与人之间传播的能力。功能增益研究与监控项目密切相关。随着科学家们发现了能够感染人类细胞的新型蝙蝠病毒，这就提出了一个问题:要使这种病毒在人类中传播，自然界必须发生什么样的变化，这将构成一种全球性的威胁。

2015年，武汉实验室利用剪贴式基因工程进行了一项功能增益实验，科学家们提取了一种天然病毒，并直接对其RNA编码进行替换，使其更易传播。他们提取了一部分最初的非典病毒，并插入了一个类似非典的蝙蝠冠状病毒片段，产生了一种能够感染人类细胞的病毒。用这些方法改变的自然病毒很容易在基因分析中被标记出来，就像维多利亚时代的老房子的当代附加物。

用动物传代方法产生的病毒将更难被发现。这些病毒不是直接操纵的。当病毒从一种动物传播到另一种动物时，它会经历一些类似于在进化过程中在野外会发生的事情。通过10只雪貂的野生冠状病毒很难被识别为是经过改造或操纵的。

武汉研究所没有关于冠状病毒动物传播工作的公开记录。该实验室在2018年获得了第一个BSL-4实验室，这被认为是这类工作的一个要求(尽管有些工作是在BSL-3增强型实验室中进行的)。有可能研究人员在BSL-4实验室开始了动物传代工作，但没有在当前的大流行之前及时完成，当时中国收紧了对出版物的限制。这项工作有可能是秘密完成的。有可能它根本没发生过。但是一些科学家认为，一个昂贵的BSL-4实验室不太可能不进行动物通道研究，这在2018年之前并不罕见。

追溯起源

为了弄清楚非典-CoV-2是从哪里来的，斯克里普斯研究公司的克里斯蒂安·安德森和他的同事们进行了一项基因分析:他们在1997年3月17日发表了这项被广泛引用的研究自然医学。研究人员集中在病毒的某些遗传特征上，寻找“操纵”的迹象。

其中一个特征是蛋白质的峰值，病毒利用这一点非常有效地附着在人体的血管紧张素转换酶2受体上，这是我们肺部和其他器官细胞的一个分子特征。作者总结道，非典-Cov-2的高峰与最初的非典病毒的不同之处在于，它“最有可能是自然选择的产物”——换句话说，是自然的，而不是在实验室中操纵的。

然而，这篇论文关于为什么动物通道可以被排除的推理并不清楚。“理论上，非典-CoV-2有可能获得了...作者写道:“在细胞培养中适应传代过程中的突变。”。这种病毒在穿山甲等哺乳动物宿主中发生突变的理论“提供了更强的...解释。”他们没有说这是否包括实验室中的动物通道。安徒生没有回应新闻周刊征求意见。

长期反对功能研究成果的罗格的Ebright说，安德森的分析未能排除动物通道是非典-CoV-2的起源。“这种推理是站不住脚的，”他在给的电子邮件中写道新闻周刊。“他们赞成‘病毒在动物宿主如穿山甲中突变’的可能性，但同时，他们不赞成病毒在‘动物传代’中突变的可能性。”因为这两种可能性是相同的，除了位置，一个不可能在逻辑上支持一个而不支持另一个。"

加州大学戴维斯分校的进化生物学家乔纳森·艾森(Jonathan Eisen)表示，大量证据虽然不是决定性的，但表明病毒来自大自然，而不是实验室。“没有迹象表明有什么不自然的东西，那就是基因工程，”他说。但是“有一些回旋的余地”的发现承认了这种病毒可能是在实验室里通过动物通道制造的。“通过测试很难。逃离实验室很难测试，”他说。“如果[武汉的研究人员]从现场收集了一些东西，并在实验室用它做了一些实验，一些人被感染，然后它从那里传播，这将很难与它在现场直接传播区分开来。”

武汉拥有一种病毒——鼠13，这种病毒被认为是所有已知病毒中最相似的——两者拥有96%的遗传物质。北卡罗来纳大学的病毒学家拉尔夫·巴里克说，这4%的差距对于动物传代研究来说仍然是一个巨大的差距，他与-李合作进行了2015年的功能获得研究。“你总是遇到一些不可能的问题，”他说。武汉可能不得不从一种更接近SARS-CoV-2而不是RATG13的病毒开始，这是有可能的。

巴里克说:“解决这个问题的唯一方法是透明和公开的科学，并对此进行一些真正的调查。我不认为中国人会允许。我不知道任何国家在这种情况下会怎么做。我想美国应该是透明的。”

詹尼·芬克为本报告供稿

THE CONTROVERSIAL EXPERIMENTS AND WUHAN LAB SUSPECTED OF STARTING THE CORONAVIRUS PANDEMIC

The coronavirus pandemic may be a result of controversial experiments inside the Wuhan Institute of Virology, as U.S. intelligence now concedes. Chinese virologist Shi Zhengli inside the P4 laboratory in Wuhan, China, on February 23, 2017. -

Just one day after the U.S. surpassed China to become the country with the highest number of Covid-19 cases, the U.S. Defense Intelligence Agency updated its assessment of the origin of the novel coronavirus to reflect that it may have been accidentally released from an infectious diseases lab, Newsweek has learned.

The report, dated March 27 and corroborated by two U.S. officials, reveals that U.S. intelligence revised its January assessment in which it "judged that the outbreak probably occurred naturally" to now include the possibility that the new coronavirus emerged "accidentally" due to "unsafe laboratory practices" in the central Chinese city of Wuhan, where the pathogen was first observed late last year. The classified report, titled "China: Origins of COVID-19 Outbreak Remain Unknown," ruled out that the disease was genetically engineered or released intentionally as a biological weapon.

"We have no credible evidence to indicate SARS-CoV-2 was released intentionally or was created as a biological weapon," the report found. "It is very unlikely that researchers or the Chinese government would intentionally release such a dangerous virus, especially within China, without possessing a known and effective vaccine." Every scientist interviewed by Newsweek for this story also rejected categorically the notion that the virus was intentionally released.

Covid-19 has infected nearly 3 million people across the globe, initially ravaging China before hitting hardest in the West and leaving the United States as the most deeply-afflicted country, with more than 55,000 deaths as of April 27. Its origin remains the subject of not only scientific debate, but a politically charged dispute in the international community.

Citing academic literature, the DIA document states that a "definitive answer may never be known" as to how the disease truly first emerged. A U.S. intelligence spokesperson told Newsweek, "the Intelligence Community has not collectively agreed on any one theory."

Uncertain source

Tracing the origin of a new virus is not easy. It took researchers at the Wuhan Institute more than a decade to trace the 2002-2003 SARS virus to remote bat caves in Yunnan province. It's not surprising, then, that in early February, China's Academy for Military Medical Sciences "concluded that it was impossible for them to scientifically determine whether the Covid-19 outbreak was caused naturally or accidentally from a laboratory incident," according to the DIA document.

Initial assessments conducted by the Chinese government pointed to the city's Huanan Seafood Market as the likely cause of a natural outbreak of SARS-CoV-2, a new coronavirus that causes Covid-19. In the early days of the outbreak, local officials played down the possibility of human-to-human transmission of the virus and silenced doctors who spoke out about the growing outbreak. It may have undercounted deaths and the number of cases of Covid-19. A spurious theory that the U.S. deliberately planted the virus in Wuhan also started circulating.

China's foreign ministry told reporters April 23rd that the World Health Organization found "no evidence" the outbreak started at the Wuhan laboratory, and Yuan Zhiming, vice president of the Wuhan Institute of Virology and president of the Chinese Academy of Sciences Wuhan Branch, blasted the inference of intentional misuse or creation as "malicious" and "impossible."

"The director of the Galveston National Laboratory in the United States made it clear that our laboratory is just as well managed as labs in Europe and the U.S.," he said. "I think it is understandable for people to make that association. But it is a malicious move to purposefully mislead the people" to think that the virus escaped from [our Wuhan] labs.

"They have no evidence or logic to support their accusations. They are basing it completely on their own speculations."

The DIA report, however, cites U.S. government and Chinese researchers that found "about 33 percent of the original 41 identified cases did not have direct exposure" to the market. That, along with what's known of the laboratory's work in past few years, raised reasonable suspicion that the pandemic may have been caused by a lab error, not the wet market.

Here's what the scientific and circumstantial evidence shows.

Back in 2002, when SARS emerged in China's Guandong province, it served as a wake-up call. Over the next few decades, the U.S., China and other nations poured money into efforts to hunt down and catalogue strange new pathogens that live in wild animals and figure out how much of a threat they pose to humans, with the goal of preventing the next devastating pandemic.

In the fall of 2019, the SARS-CoV-2 coronavirus emerged in the middle of the large, cosmopolitan city of Wuhan. Chinese officials at first insisted that the virus, SARS-CoV-2, could be caught only through direct contact with animals. But many of the early patients in Wuhan had no connection to the wild animal markets, which meant that the virus had already been spreading from person to person. When this fact came out, it cast doubt on the veracity of information coming from China, but the virus was well on its way to becoming a deadly pandemic.

In the early days, the prevailing theory of the virus' origins was that it, like SARS, arose in bats, passed to some other mammal such as a pangolin, and ultimately entered the population through the wild-animal markets.

By March, the wild-virus theory was still the most likely explanation of the origin of SARS-CoV-2--but it was starting to look a little ragged around the edges. For one thing, the Wuhan Institute of Virology, not far from the animal markets in downtown Wuhan, houses the world's largest collection of coronaviruses from wild bats, including at least one virus that bears a resemblance to SARS-CoV-2. What's more, Wuhan Institute of Virology scientists have for the past five years been engaged in so-called "gain of function" (GOF) research, which is designed to enhance certain properties of viruses for the purpose of anticipating future pandemics. Gain-of-function techniques have been used to turn viruses into human pathogens capable of causing a global pandemic.

This is no nefarious secret program in an underground military bunker. The Wuhan lab received funding to do this work in part from a ten-year, $200 million international program called PREDICT, funded by the U.S. Agency for International Development and other countries. Similar work, funded in part by the U.S. National Institutes of Health, has been carried out in dozens of labs throughout the world. Some of this research involves taking deadly viruses and enhancing their ability to spread quickly through a population—research that took place over the objections of hundreds of scientists, who have warned for years of the program's potential to cause a pandemic.

In the years since the SARS outbreak, many instances of mishaps involving the accidental release of pathogens have taken place in labs throughout the world. Hundreds of breaches have occurred in the U.S., including a 2014 release of anthrax from a U.S. government lab that exposed 84 people. The SARS virus escaped from a Beijing lab in 2004, causing four infections and one death. An accidental release is not complicated and doesn't require malicious intent. All it takes is for a lab worker to get sick, go home for the night, and unwittingly spread the virus to others.

The Wuhan Institute has a record of shoddy practices that could conceivably lead to an accidental release, as officials at the U.S. Embassy in Beijing reportedly warned in a cable on January 19, 2018. "During interactions with scientists at the WIV laboratory, they noted the new lab has a serious shortage of appropriately trained technicians and investigators needed to safely operate this high-containment laboratory," states the cable, according to the Washington Post.

To be sure, there's no evidence that SARS-Cov-2 came from the Wuhan lab, nor that the virus is the product of engineering. Most scientists believe, based on the evidence available, that a natural origin is the most likely explanation. But neither have they ruled out these possibilities. "At this stage, it is not possible to determine precisely the source of the virus which caused the COVID-19 pandemic," says the World Health Organization in a statement to Newsweek. "All available evidence suggests that the virus has a natural animal origin and is not a manipulated or constructed virus."

The circumstantial evidence is strong enough to warrant putting the lab's programs and practices at the heart of the investigation. And it's worth looking anew at whether scientists, in their efforts to protect the public from the threat of natural pathogens, overreached.

Animal Passage

Ten years ago, the viral pathogen most in the news was not a coronavirus but influenza—in particular, a strain of flu, designated H5N1, that arose in birds and killed a high proportion of those who were infected. For a while, the virus made headlines. Then it became clear that nearly everyone who caught the bird-flu virus got it directly from handling birds. To cause a plague, it's not enough that a virus is an efficient killer. It also has to pass easily from one person to the next, a quality called transmissibility.

Around this time, Ron Fouchier, a scientist at Erasmus University in Holland, wondered what it would take for the bird flu virus to mutate into a plague virus. The question was important to the mission of virologists in anticipating human pandemics. If H5N1 were merely one or two steps away from acquiring human transmissibility, the world was in danger: a transmissible form of H5N1 could quickly balloon into a devastating pandemic on the order of the 1918 flu, which killed tens of millions of people.

To answer the question, scientists would have to breed the virus in the lab in cell cultures and see how it mutated. But this kind of work was difficult to carry out and hard to draw conclusions from. How would you know if the end result was transmissible?

The answer that Fouchier came up with was a technique known as "animal passage," in which he mutated the bird-flu virus by passing it through animals rather than cell cultures. He chose ferrets because they were widely known as a good stand-in for humans—if a virus can jump between ferrets, it is likely also to be able to jump between humans. He would infect one ferret with a bird-flu virus, wait until it got sick, and then remove a sample of the virus that had replicated in the ferret's body with a swab. As the virus multiplies in the body, it mutates slightly, so the virus that came out of the ferret was slightly different from the one that went into it. Fouchier then proceeded to play a version of telephone: he would take the virus from the first ferret and infect a second, then take the mutated virus from the second ferret and infect a third, and so on.

After passing the virus through 10 ferrets, Fouchier noticed that a ferret in an adjacent cage became ill, even though the two hadn't come into contact with one another. That showed that the virus was transmissible in ferrets—and, by implication, in humans. Fouchier had succeeded in creating a potential pandemic virus in his lab.

When Fouchier submitted his animal-passage work to the journal Science in 2011, biosecurity officials in the Obama White House, worried that the dangerous pathogen could accidentally leak from Fouchier's lab, pushed for a moratorium on the research. Fouchier had done his work in BSL-2 labs, which are intended for pathogens such as staph, of moderate severity, rather than BSL-4, which are intended for Ebola and similar viruses. BSL-4 labs have elaborate safeguards—they're usually separate buildings with their own air circulation systems, airlocks and so forth. In response, the National Institutes of Health issued a moratorium on the research.

What followed was a fierce debate among scientists over the risks versus benefits of the gain-of-function research. Fouchier's work, wrote Harvard epidemiologist Marc Lipsitch in the journal Nature in 2015, "entails a unique risk that a laboratory accident could spark a pandemic, killing millions."

Lipsitch and 17 other scientists had formed the Cambridge Working Group in opposition. It issued a statement pointing out that lab accidents involving smallpox, anthrax and bird flu in the U.S. "have been accelerating and have been occurring on average over twice a week."

"Laboratory creation of highly transmissible, novel strains of dangerous viruses... poses substantially increased risks," the statement said. "An accidental infection in such a setting could trigger outbreaks that would be difficult or impossible to control. Historically, new strains of influenza, once they establish transmission in the human population, have infected a quarter or more of the world's population within two years." More than 200 scientists eventually endorsed the position.

The proponents of gain-of-function research were just as passionate. "We need GOF experiments," wrote Fouchier in Nature, "to demonstrate causal relationships between genes or mutations and particular biological traits of pathogens. GOF approaches are absolutely essential in infectious disease research."

The NIH eventually came down on the side of Fouchier and the other proponents. It considered gain-of-function research worth the risk it entailed because it enables scientists to prepare anti-viral medications that could be useful if and when a pandemic occurred.

By the time NIH lifted the moratorium, in 2017, it had granted dozens of exceptions. The PREDICT program, started in 2009, spent $200 million over 10 years, sending virologists all over the world to look for novel viruses and perform gain-of-function research on them. The program's funding ran out in 2018 and it wasn't renewed. Early this year, after the Trump administration drew criticism for canceling the program, it granted a six-month extension.

By the time the current pandemic hit, animal-passage experiments had become commonplace. Scientists in many of the more than 30 BSL-4 labs around the world had used them to enhance the transmissibility of respiratory-tract pathogens.

Did the work help during the current pandemic? In a recent article in the Lancet, Colin Carlson, an expert in emerging infectious diseases at Georgetown University, argued that work funded by PREDICT helped virologists rapidly isolate and classify the SARS-CoV-2 virus when it came out. However, the research "could have been better positioned for an overall impact." Although the program found hundreds of new viruses, it's nearly impossible for scientists to assess their risk to humans. The only way to tell is to "observe a human infection."

Richard Ebright, an infectious disease expert at Rutgers, put it more bluntly. "The PREDICT program has produced no results—absolutely no results—that are of use for preventing or combating outbreaks. There's no information from that project that will contribute in any way, shape or form to addressing the outbreak at hand. The research does not provide information that's useful for developing antiviral drugs. It does not provide information that's useful for developing vaccines."

The Wuhan Institute of Virology, not far from the animal markets in downtown Wuhan, houses the world’s largest collection of coronaviruses from wild bats. The facility is among a handful of labs around the world cleared to handle Class 4 pathogens (P4) - dangerous viruses that pose a high risk of person-to-person transmission.

China's role

The Wuhan Institute of Virology is one of many labs to receive PREDICT funding. Shi Zheng-Li, a virologist known as "bat woman" for her group's work in collecting hundreds of coronaviruses, and her staff at the Institute explored the same bat caves that were thought to have given rise to the original SARS virus in 2002. Her scientists penetrated remote caves, swabbing bats' anuses and collecting their excretions. When they returned to the lab, they cultured the viruses they found, determined their genomic sequences and tried to determine how they infect cells and animals in the lab.

The Institute began a program of gain-of-function research into bat coronaviruses in 2015. That involved taking selected strains and seeking to increase the ability of those viruses to transmit from one person to another. The gain-of-function research went hand-in-hand with the surveillance project. As scientists identified new classes of bat viruses that have the ability to infect human cells, that raised the question of what changes would have to arise in nature to make that virus transmissible in humans, which would pose a pandemic threat.

In 2015, the Wuhan lab performed a gain of function experiment using cut-and-paste genetic engineering, in which scientists take a natural virus and directly make substitutions in its RNA coding to make it more transmissible. They took a piece of the original SARS virus and inserted a snippet from a SARS-like bat coronavirus, resulting in a virus that is capable of infecting human cells. A natural virus altered with these methods would be easily flagged in a genetic analysis, like a contemporary addition to an old Victorian house.

A virus produced with animal passage methods would be much harder to spot. These viruses are not directly manipulated. When the virus passes from one animal to the next, it undergoes something similar to what would happen in the wild during the course of its evolution. A wild coronavirus passed through 10 ferrets would be difficult to identify as having been engineered or manipulated.

There is no published record of animal-passage work on coronaviruses in the Wuhan Institute. The lab got its first BSL-4 lab in 2018, which is now considered a requirement for this kind of work (though some work proceeds in BSL-3-enhanced labs). It's possible that researchers started animal passage work in the BSL-4 lab but didn't finish it in time to publish before the current pandemic, when China tightened up on publications. It's possible that the work was done in secret. It's possible that it never happened at all. But some scientists think it's unlikely that an expensive BSL-4 lab would not be doing animal-passage research, which by 2018 was not unusual.

Tracing the origins

To figure out where SARS-CoV-2 came from, Kristian Andersen of Scripps Research and his colleagues performed a genetic analysis: they published the work, which has been widely cited, on March 17 in Nature Medicine. The researchers focused on certain genetic features of the virus for telltale signs of "manipulation."

One feature was the spike of protein that the virus uses to attach so effectively to the human body's ACE2 receptors, a molecular feature of the cells in our lungs and other organs. The spike in SARS-Cov-2, the authors conclude, differs from that of the original SARS virus in ways that suggest it was "most likely the product of natural selection"—in other words, natural, not manipulated in a lab.

However, the paper's reasoning as to why animal passage, in particular, can be ruled out, is not clear. "In theory, it is possible that SARS-CoV-2 acquired the... mutations during adaptation to passage in cell culture," the authors write. The theory that the virus mutated in mammalian hosts such as pangolins "provides a much stronger... explanation." Whether or not that includes animal passage in a lab, they don't say. Andersen didn't respond to Newsweek requests for comment.

Rutger's Ebright, a longtime opponent of gain of function research, says that the Andersen analysis fails to rule out animal-passage as an origin of SARS-CoV-2. "The reasoning is unsound," he wrote in an email to Newsweek. "They favor the possibility 'that the virus mutated in an animal host such as a pangolins' yet, simultaneously, they disfavor the possibility that the virus mutated in 'animal passage.' Because the two possibilities are identical, apart from location, one can't logically favor one and disfavor the other."

Jonathan Eisen, an evolutionary biologist at UC Davis, says that the preponderance of evidence, while not definitive, suggests that the virus came from nature, not a lab. "There's no hint there that there's something unnatural, that is, genetically engineered," he says. But "there is some wiggle room" in the findings that admits the possibility that the virus was concocted in a lab via animal passage. "Passaging is hard to test for. Escape from a lab is hard to test for," he says. "If [Wuhan researchers] collected something from the field and they were doing some experiments in the lab with it, and some person got infected and then it spread from there, that would be really hard to distinguish from it having spread in the field directly."

Wuhan is in possession of a virus, RATG13, that is thought to be the most similar to SARS-CoV-2 of any known virus—the two share 96 percent of their genetic material. That four-percent gap would still be a formidable gap for animal-passage research, says Ralph Baric, a virologist at the University of North Carolina who collaborated with Shi Zheng-Li on the 2015 gain-of-function research. "You keep running into problems that just don't make it likely," he says. Wuhan would probably have had to start with a virus closer to SARS-CoV-2 than RATG13, which is within the realm of possibilities.

"The only way to resolve it," says Baric, "is transparency and open science and have some real investigation into it. I don't think the Chinese are going to allow that. I don't know what any country would do in this situation. I would like to think that the U.S. would be transparent."

Jenni Fink contributed to this report