产生大流行潜在病原体的研究为何如此

Examples of potential pandemic pathogens (PPP) include the influenza virus, SARS, and MERS — pathogens that may evolve into a pandemic. Gain-of-function (GOF) experiments, therefore, aim to emulate the evolution of a pathogen — such as in gaining virulence, infectivity, or transmissibility — to study what potential outbreaks or pandemics might look like. But is it wise to perform such GOF research?

潜在的流感大流行的病原体(PPP) 电子 xamples 包括流感病毒，SARS和MERS -这可能演变成流感大流行的病原体。 因此，功能增益(GOF)实验旨在模拟病原体的进化过程(例如获得毒力，传染性或传播性)，以研究潜在爆发或大流行的情况。 但是进行这样的GOF研究是否明智？

GOF实验如何完成 (How GOF experiments are done)

GOF research can be done with two methods — site-directed mutagenesis and serial passaging.

GOF研究可以通过两种方法完成：定点诱变和连续传代。

Site-directed mutagenesis makes intentional changes in specific locations of a gene sequence. In essence, this genetic engineering technique artificially induces mutations in an organism. Such a process also leaves a ‘mark’ in the genome, which can be detected with other genetic tools. Therefore, any human-manipulated genomes can always be caught.

定点mutagenesi 小号品牌的基因序列的特定位置的人为改变。 本质上，这种基因工程技术是人为地诱导生物体内的突变。 这样的过程还在基因组中留下了“标记”， 可以用其他遗传工具来检测 。 因此，任何人类操纵的基因组都可以随时被捕获。

Passaging means infecting a set of cells or animals with a microbe that it has not encountered to accelerate natural evolution and adaptation in a new environment. Passaging is often done in iterations — serial passage — to gradually modify a specific microbial function. As serial passaging mimics natural evolution in a new environment, it does not count as genetic engineering and does not leave any fingerprint in the organism’s genome.

传代意味着用一种微生物感染一组细胞或动物，而这种微生物在加速在新环境中的自然进化和适应过程中还没有遇到。 传代通常是在迭代(串行传代)中完成的，以逐步修改特定的微生物功能。 由于连续传代模仿了新环境中的自然进化，因此它不算作基因工程， 并且不会在生物体的基因组中留下任何指纹。

GOF研究历史简述 (History of GOF research in brief)

第一部分：2011年有争议的出版物 (Part I: 2011 controversial publications)

In 2011, the National Science Advisory Board for Biosecurity (NSABB) halted the publication of two GOF studies involving the H5N1 influenza virus, which were the most controversial research ever done at that time.

2011年，美国国家生物安全科学咨询委员会(NSABB)停止发布两项涉及H5N1流感病毒的GOF研究，这是当时有争议的研究。

Two separate research groups in the Netherlands and U.S. induced mutations in the H5N1 influenza virus genome and then passaged it in ferrets for multiple iterations to achieve airborne spread. Such GOF research warns that H5N1 influenza, which does not spread among humans, could evolve an aerosol transmission ability in mammals. “And thus pose a risk of becoming pandemic in humans,” concluded one of the studies.

荷兰和美国的两个独立研究小组在H5N1流感病毒基因组中诱导了突变，然后将其传到雪貂中进行多次迭代以实现机载传播。 GOF的此类研究警告说，不会在人类中传播的H5N1流感可能会在哺乳动物中发展气雾传播能力。 其中一项研究总结说：“因此有可能导致人类大流行。”

“Scientists believe it’s likely that the pathogen, if it emerged in nature or were released, would trigger an influenza pandemic, quite possibly with many millions of deaths,” Science reported. “[It’s] probably one of the most dangerous viruses you can make.” Further, the methods sections of those studies might give potential terrorists the blueprint to create bioweapons.

“科学家认为，这种病原体如果自然界中出现或被释放，很可能引发流感大流行，很可能导致数百万人死亡，”《 科学》 报道 。 “ [它]可能是您可以制造的最危险的病毒之一。” 此外，这些研究的方法部分可能为潜在的恐怖分子提供了制造生物武器的蓝图。

After intense debate, however, the NSABB reasoned that the benefits outweighed the risks. Both studies were ultimately published in 2012 in Science and Nature.

但是，经过激烈的辩论，NSABB 认为收益大于风险。 两项研究最终于2012年发表在《 科学》杂志上 与自然 。

第二部分：2014年实验室事故和GOF研究暂停 (Part II: 2014 lab accidents and suspension of GOF research)

As long as such GOF experiments are done safely, then all are fine. However, records of lab accidents, even in the most advanced government laboratories, have raised more concerns about the continuation of GOF research. There are such three examples in 2014 in the U.S. alone:

只要可以安全地进行此类GOF实验，那么一切都很好。 但是，即使在最先进的政府实验室中，实验室事故的记录也引起了人们对GOF研究持续性的更多关注。 仅在美国，2014年就有以下三个例子：

1. In the Centers for Disease Control and Prevention (CDC) Anthrax lab incident, workers handled live Anthrax bacterium that was thought to be dead because scientists did not inactivate the bacteria properly before leaving the lab. About 70 workers possibly exposed to Anthrax were treated with antibiotics and vaccinations, and nobody fell ill.

   在疾病控制与预防中心(CDC) 炭疽病实验室事件中 ，工作人员处理了被认为已经死亡的活炭疽细菌，因为科学家在离开实验室之前并未适当地使细菌失活。 大约有70名可能接触炭疽的工人接受了抗生素和疫苗的治疗，没有人生病。

2. In the CDC influenza lab incident, the shipment of a harmless H9N2 influenza strain to the USDA poultry lab was contaminated with a dangerous H5N1 influenza strain, although nobody got sick.

   在CDC流感实验室事件中 ，向美国农业部家禽实验室运送的无害H9N2流感病毒株被危险的H5N1流感病毒株污染，尽管没有人生病。

3. In the National Institutes of Health (NIH) smallpox lab incident, six vials of the lethal variola virus were found in the FDA laboratory for low-risks research at the NIH. The vials might have been there since the 1960s and were immediately transferred to the CDC-registered containment laboratory in Bethesda before any disaster happens.

   在美国国立卫生研究院(NIH)天花实验室事件中 ，在FDA实验室中发现了六瓶致命天花病毒，用于NIH的低风险研究。 这些小瓶可能自1960年代就已经在那里，并在发生任何灾难之前立即转移到了CDC注册的贝塞斯达遏制实验室。

As a result, over 200 researchers signed the “Cambridge Working Group Consensus Statement on the Creation of Potential Pandemic Pathogens (PPPs)” in 2014 that pleads for the cessation of GOF experiments. This statement persuaded U.S. President Barack Obama and the NIH to stop funding GOF research on PPP in 2014.

结果，超过200名研究人员在2014年签署了“ 剑桥工作组关于创建潜在大流行病原体(PPPs)的共识声明 ”，呼吁停止GOF实验。 该声明说服美国总统巴拉克·奥巴马(Barack Obama)和美国国立卫生研究院(NIH)在2014年停止资助政府对PPP的研究。

Accidental escapes of pathogens belong to the biosafety category. The biosecurity side, in contrast, concerns the risk of bioterrorism acts that exploit the knowledge or material gained from GOF research.

病原体的意外逸出属于生物安全类别。 相比之下，生物安全方面关注利用从GOF研究中获得的知识或材料的生物恐怖主义行为的风险。

第三部分：GOF研究的2017年批准 (Part III: 2017 approval of GOF research)

After a few years of revising research policies, the NIH announced in December 2017 that GOF studies are allowed to continue if it gets approved by the review board of the Department of Health and Human Services (HHS), which also now supervises GOF experiments as they proceed.

经过几年的研究政策修订， NIH于2017年12月宣布 ，如果GOF研究得到卫生和公共服务部(HHS)审查委员会的批准，则可以继续进行GOF研究，该委员会现在还对GOF实验进行监督继续。

How does the HHS decide whether to approve a GOF study or not? “The first question is: how likely is the research to result in benefits and how great would these benefits be, and how likely is the research to result in harm, and how great would these harms be?” Michael Selgelid, a professor of bioethics and director of the Centre for Human Bioethics at Monash University and the WHO Collaborating Centre for Bioethics, explained in 2018.

HHS如何决定是否批准GOF研究？ “第一个问题是：这项研究产生收益的可能性有多大？这些收益有多大？该研究产生损害的可能性有多大？这些损害有多大？” 莫纳什大学生物伦理学教授兼人类生物伦理学中心主任和世卫组织生物伦理学合作中心主任迈克尔·塞尔吉利德(Michael Selgelid)在2018年作了解释 。

“But risk-benefit assessment is not an exact science, nor is it perfectly objective — a lot of the time, it is going to be very difficult to say what constitutes a situation where the benefits outweigh the risks,” the professor continued.

这位教授继续说道：“但是，风险收益评估并不是一门精确的科学，也不是完全客观的。在很多时候，要说出什么是收益大于风险的情况是很难的。”

Regardless, the scientific community has settled on the consensus that certain GOF research is worth investigating as they bring value that offsets potential risks. So, what are the risks and benefits of such research?

无论如何，科学界已经达成共识，认为某些GOF研究值得研究，因为它们带来的价值可以抵消潜在风险。 那么，这种研究的风险和收益是什么？

GOF研究的风险 (Risks of GOF Research)

Microbes can leak from labs. Over 1100 cases of unintended leakage of microbes or toxins with potential public health risks happened between 2008 to 2012. “More than 200 incidents of loss or release of bioweapons agents from U.S. laboratories are reported each year,” said Richard Ebright, a professor of chemistry and chemical biology at the Rutgers University and head of the Waksman Institute of Microbiology, who also testified before Congress about the CDC’s lab accidents in 2014.

微生物会从实验室泄漏。 化学教授理查德·埃布赖特(Richard Ebright)说，在2008年至2012年之间，发生了1100多起意外的微生物或毒素意外泄漏事件，这些微生物或毒素具有潜在的公共卫生风险。“每年美国实验室报告的生物武器剂损失或释放事件超过200起，”罗格斯大学化学与生物学专业和瓦克斯曼微生物研究所所长，他还向国会作证了CDC 2014年的实验室事故。

Other well-known lab escapes of pathogens include the H1N1 swine flu in 1977, smallpox in the 1970s, Venezuelan equine encephalitis in 1995, SARS (six separate incidents) after the 2003 epidemic, foot and mouth disease in 2007, and possibly Covid-19.

其他著名的实验室病原体逃逸措施包括1977年的H1N1猪流感，1970年代的天花，1995年的委内瑞拉马脑炎，2003年流行后的SARS(六次独立事件)，2007年的手足口病以及Covid-19 。

“Scientists believe it’s likely that the pathogen, if it emerged in nature or were released, would trigger an influenza pandemic, quite possibly with many millions of deaths.”

“科学家认为，这种病原体如果自然界中出现或被释放，很可能引发流感大流行，很可能造成数百万人死亡。”

Accidental escapes of pathogens belong to the biosafety category. The biosecurity side, in contrast, concerns the risk of bioterrorism acts that exploit the knowledge or material gained from GOF research. While the risks of lab accidents can be predicted with historical records and minimized with proper facilities and safety measures, it is not the case for bioterrorism.

病原体的意外逸出属于生物安全类别。 相比之下，生物安全方面关注利用从GOF研究中获得的知识或材料的生物恐怖主义行为的风险。 虽然可以通过历史记录来预测实验室事故的风险，并可以通过适当的设施和安全措施将其降到最低，但是生物恐怖主义并非如此。

“Biosecurity estimates are difficult, because they involve a calculation of the risk of deliberate nefarious action, and such information is simply not always available,” said a 2014 research review of Arturo Casadevall, a distinguished professor of molecular microbiology, immunology, and infectious diseases at the Johns Hopkins Bloomberg School of Public Health and Medicine. “In fact, these assessments are so difficult that we have called for the formation of a national board to handle questions related to dual-use research of concern,” which means research that has both beneficial and malicious applications.

“生物安全性估算是困难的，因为它们涉及到有意进行恶意行为的风险的计算，而这种信息根本不总是可用，”分子微生物学，免疫学和传染病学杰出教授Arturo Casadevall在2014年的研究评论中说。在约翰霍普金斯大学彭博公共卫生学院。 “实际上，这些评估非常困难，以至于我们呼吁成立一个国家委员会来处理与所关注的双重用途研究有关的问题，”这意味着该研究既有有益的应用，也有恶意的应用。

GOF研究的好处 (Benefits of GOF research)

GOF research could determine which viral gene or protein is responsible for a specific function. It answers if “a particular set of genetic changes [is] sufficient to create a particular phenotype…?” stated a 2018 research review of Marc Lipsitch, a professor of epidemiology and director of the Center for Communicable Disease Dynamics at the Harvard T.H. Chan School of Public Health. “This question can be answered only by a GOF experiment because if one does not create the phenotype, one cannot measure it.”

GOF研究可以确定哪种病毒基因或蛋白质负责特定功能。 它回答“是否有一组特定的遗传变化足以产生特定的表型……？” 哈佛大学陈赞公共卫生学院流行病学教授，传染病动态中心主任马克·利普西奇(Marc Lipsitch) 在2018年发表了一项研究评论 。 “这个问题只能通过GOF实验来回答，因为如果不创建表型，就无法对其进行测量。”

(Phenotype refers to a particular trait of an organism, such as virulence.)

(表型是指生物体的特定特征，例如毒力。)

“GOF-type experiments are of particular epistemological value because they directly imply causality,” agreed Prof. Casadevall et al. “The power of GOF experiments is that they are a highly efficient, reliable, and effective tool that can identify certain phenotypes that often cannot be identified by using other scientific approaches.”

Casadevall教授等同意：“ GOF型实验具有特殊的认识论价值，因为它们直接暗示了因果关系。” “ GOF实验的强大之处在于它们是一种高效，可靠和有效的工具，可以识别某些表型，而这些表型通常是使用其他科学方法无法识别的。”

“Information garnered from basic influenza virus research, including GOF studies…has benefited public health and the vaccine production process in numerous ways.”

“从基础流感病毒研究(包括GOF研究)中获得的信息……以多种方式有益于公共卫生和疫苗生产过程。”

Early disease control actions such as animal culling or designs of vaccines or antimicrobials can, thus, be catered to those set of genes or proteins (or phenotype) that pose a threat to humans. “Gain-of-function experiments allow us to understand how pandemic viruses evolve so that we can make predictions, develop countermeasures, and do disease surveillance,” Carrie Wolinetz, a director of the NIH Office of Science Policy, explained.

因此，可以控制早期疾病控制措施，例如动物淘汰或设计疫苗或抗菌剂，以应对那些对人类构成威胁的基因或蛋白质(或表型)。 美国国立卫生研究院科学政策办公室主任Carrie Wolinetz 解释说： “获得功能的实验使我们能够了解大流行性病毒是如何进化的，以便我们可以做出预测，制定对策和进行疾病监测。”

In fact, it is such GOF research that assists in the preparation of seasonal flu vaccines. “Selection of viruses chosen for CVV [candidate vaccine virus] generation, pilot lot production, and, ultimately, inclusion in the national or global stockpiles are often made with consideration of GOF mutations identified during molecular risk assessment so that viruses with the greatest pandemic potential are selected,” scientists at the WHO Collaborating Center for Influenza Research detailed in a 2014 paper. “Information garnered from basic influenza virus research, including GOF studies…has benefited public health and the vaccine production process in numerous ways.”

实际上，正是这样的GOF研究有助于制备季节性流感疫苗。 “选择用于CVV [候选疫苗病毒]产生，中试批次生产以及最终包括在国家或全球储备中的病毒的选择，通常要考虑到在分子风险评估过程中发现的GOF突变，从而使具有大流行潜力的病毒成为可能。是由世界卫生组织流感研究合作中心的科学家在2014年的一篇论文中详细介绍的 。 “从基础流感病毒研究(包括GOF研究)中获得的信息……以多种方式有益于公共卫生和疫苗生产过程。”

简短摘要和结束语 (Short abstract and closing)

Gain-of-function (GOF) research, especially on potential pandemic pathogens (PPP), has sparked controversies in 2011 and faced suspension from 2014 to 2017. However, the risk-benefit analyses by health authorities underscored that GOF research still brings more value than its probable risks. As Prof. Casadevall and others concluded, “Think about both risks and benefits, take obvious precautions, and then make the prudent choice. With enhanced biosafety protocols and improvements in the public health response, we should not ban GOF research but monitor it,”

功能获得(GOF)研究，尤其是关于潜在大流行病原体(PPP)的研究，在2011年引发了争议，并在2014年至2017年面临停工。但是，卫生当局的风险收益分析强调，GOF研究仍可带来更多价值超过其可能的风险。 正如Casadevall教授和其他人得出的结论：“既要考虑风险也要考虑收益，采取明显的预防措施，然后做出谨慎的选择。 随着增强的生物安全协议和公共卫生对策的改善，我们不应禁止GOF研究，而应对其进行监控，”