[搬运工]Science关于Omicron起源的好文一篇（配独家点评）

大家好，

昨天的那篇定心丸小文章，

那个是我自己删的（不是被搞了）。

原因很简单，

咱膨胀了，

在没做足功课的情况下直接下笔八卦不熟悉的领域，

然后被后台评论啪啪打脸。

下次咱一定注意，

就算要膨胀，

也只在熟悉的舒适区里略微膨胀……

就比如说下面要搬运的这篇新鲜出炉的《Science》文章，

咱不仅打算搬运过来，

凑个双更，

算是补上昨晚上被删的那一份儿~

咱还打算顺便斗胆点评两句，

各位以为如何？

下面就请各位品鉴~

Omicron这奇葩货到底是哪儿来的？

突变积累的罪魁祸首可能是长期感染病例、人群隐匿传播，或是动物宿主

Since South African scientists announced last week they had identified an unsettling new variant of SARS-CoV-2, the world has anxiously awaited clues about how it might change the trajectory of the pandemic. But as big a mystery—if less urgent—is where and how Omicron evolved, and what lessons its emergence holds for avoiding future dangerous variants.

Omicron clearly did not develop out of one of the earlier variants of concern, such as Alpha or Delta. Instead, it appears to have evolved in parallel—and in the dark. Omicron is so different from the millions of SARS-CoV-2 genomes that have been shared publicly that pinpointing its closest relative is difficult, says Emma Hodcroft, a virologist at the University of Bern. It likely diverged early from other strains, she says. “I would say it goes back to mid-2020.”

That raises the question of where Omicron’s predecessors lurked for more than a year. Scientists see essentially three possible explanations: The virus could have circulated and evolved in a population with little surveillance and sequencing. It could have gestated in a chronically infected COVID-19 patient. Or it might have evolved in a nonhuman species, from which it recently spilled back into people.

自从南非科学家上周宣布，他们发现了一种全新的阴间变异株以来，全世界都在关注这货到底怎样改变大流行的走向。除此之外呢，还有一个不那么紧迫的谜题，那就是——这货到底是从啥地方蹦跶出来的？又有怎样惊心动魄的演化历程？以及人类应该汲取怎样的教训以避免类似阴间变异株再次出现？

Omicron的来源显然不是之前的四大VOC，正好相反，它似乎暗搓搓地平行演化出来的。之前咱搬运过的Emma Hodcroft老师表示，Omicron跟GISAID数据库上面几百万份测序记录都大相径庭，以至于很难确定其近亲。她说，这玩意儿可能很早就与其他变异株发生了演化分支。“我觉着这玩意儿可以追溯回2020年中期。”

所以问题就来了，为啥这货可以潜伏一年多而不为人所知？大佬们基本上倾向于三种可能的解释：首先，该病毒可能在几乎没有检测和测序的人群中隐匿传播并持续演化；然后，它可能和长期感染病例有关；以及，它可能在非人类物种中演化成形，最近又回传给了人类。

——演化树也表示，亲属关系证明如下：

哦对了，这个神秘近亲的NTD部分，

也就是G142L、V143N、Y144N这几个突变，

也超级有趣，

虽然这部分跟Omicron完全不一样，

但怎么看怎么都像是个大型重组现场……

——请品鉴：

而Omicron的138-147部分，

刚好也有点像重组结果……

——请品鉴：

有趣有趣真有趣~

Christian Drosten, a virologist at Charité University Hospital in Berlin, favors the first possibility. “I assume this evolved not in South Africa, where a lot of sequencing is going on, but somewhere else in southern Africa during the winter wave,” he says. “There were a lot of infections going on for a long time and for this kind of virus to evolve you really need a huge evolutionary pressure.”

But Andrew Rambaut of the University of Edinburgh can’t see how the virus could have stayed hidden in a group of people for so long. “I'm not sure there's really anywhere in the world that is isolated enough for this sort of virus to transmit for that length of time without it emerging in various places,” he says.

Instead, Rambaut and others propose the virus most likely developed in a chronically infected COVID-19 patient, likely someone whose immune response was impaired by another illness or a drug. When Alpha was first discovered in late 2020, that variant also appeared to have acquired numerous mutations all at once, leading researchers to postulate a chronic infection. The idea is bolstered by sequencing of SARS-CoV-2 samples from some chronically infected patients.

德国病毒学大佬 Christian Drosten老师表示支持上述第一种可能性。“我认为这货的起源不是南非，因为南非测序搞得还行，应该是在Delta那一波大爆发期间南部非洲其他地方养出了妖孽，”他说。“这些地方在很长时间内都保持了高传播水平，而要演化出Omicron这样的毒王，真的需要硕大无朋的选择压力。”

但爱丁堡大学大佬 Andrew Rambaut表示，他没法理解病毒是如何在人群中隐匿传播这么久的。他说：“我不确定世界上是不是真的有这种世外桃源，足够让病毒圈地自萌如此长时间，而不会在其他地方冒头。”

相反，Rambaut老师等人提出，这货最有可能是在长期感染病例身上养蛊养出来的……这类病例的免疫系统可能因为其他疾病或药物而受损，因此无法迅速清除体内病毒。当初Alpha刚刚冒头的时候，似乎也同时获得了不少突变，这使得研究人员倾向于相信长期感染的可能性。而其他长期感染者的测序结果似乎也支持这一结论。

“I think the evidence supporting it is becoming stronger,” says Richard Lessells, an infectious disease researcher at the University of KwaZulu-Natal. In one case Lessells and his colleagues described in a preprint, a young woman in South Africa with an uncontrolled HIV infection carried SARS-CoV-2 for more than 6 months. The virus accumulated many of the same changes seen in variants of concern, a pattern also seen in another patient whose SARS-Cov-2 infection persisted even longer.

To head off one possible source of future variants, Lessells says, “What we need to do is close the gaps in the HIV treatment cascade. So we need to get everybody diagnosed, we need to get everybody on to treatment, and we need to get those that are currently on ineffective treatment on to effective treatment regimens.”

But Drosten says experience with chronic infections of influenza and other viruses in immunosuppressed patients argues against this hypothesis for Omicron. Variants that elude the immune system do develop in such people, but they come with a host of other changes that make them less able to transmit from person to person. “These viruses have very low fitness out in the real world.” That’s because the mutations allowing a virus to survive in one individual over time may be very different from those needed to best spread from one person to the next.

“我认为支持长期感染的证据越来越强，”夸祖鲁-纳塔尔大学的Richard Lessells老师表示。Lessells老师他们在一个预印本里面描述了南非某年轻女性HIV携带者，长期感染新冠病毒超过6个月。后来病毒在她体内积累出了不少VOC同款突变，而这种现象也在其他HIV携带者身上出现过。

“为了预防这类突变积累现象”，Lessells老师说，“我们需要缩小HIV感染者治疗可及性方面的差距。所以我们需要让每个人都得到诊断、接受治疗，并且接受的是有效治疗。”

但Drosten老师表示，免疫缺陷病例在发生流感或者其他病毒长期感染现象时的表现不大支持Omicron诞生于长期感染的假说。“这些免疫缺陷人群身上确实会出现免疫逃逸类突变，但同时也会出现其他突变，使得这类变异株不太适合跨宿主传播。这些养蛊养出来的变异株在现实世界中适应度非常低。这是因为长期养蛊养出来的适合体内适应性竞争的突变似乎不同于那些在跨宿主传播方面有优势的突变。

Jessica Metcalf, an evolutionary biologist at the Institute of Advanced Study in Berlin, isn’t so sure that is true for SARS-CoV-2. “I think one reason that this virus has done so well is that better binding to ACE2 [its receptor on human cells] helps for both within-host spread and between-host spread.” Still, for the moment, she agrees with Drosten that Omicron most likely circulated and evolved in a hidden population.

Some think the virus might have hidden in rodents or other animals, rather than people, and therefore experienced different evolutionary pressures that selected for novel mutations. “The genome is just so weird,” says Kristian Andersen, an infectious disease researcher at Scripps Research, pointing to its medley of mutations, many of which have not been seen before in other variants

.“It is interesting, just how crazily different it is,” says evolutionary biologist Mike Worobey of the University of Arizona, Tucson. Although he favors an immunosuppressed person as the source of Omicron, Worobey notes that 80% of white-tailed deer sampled in Iowa between late November 2020 and early January 2021 carried SARS-CoV-2, according to a recent preprint. “It does make me wonder if other species out there can become chronically infected, which would potentially provide this sort of selective pressure over time.”

柏林高级研究所的演化生物学家Jessica Metcalf老师表示她不太确定新冠病毒在长期感染者体内的演化路径是否跟流感之类的差不多。“我认为Omicron发挥如此惊人的原因之一，在于它可以更好地结合ACE2受体，而这一特点同时有助于宿主内传播和宿主间传播。”不过，就目前而言，她表示同意Drosten老师的观点，即 Omicron很可能是在某些世外桃源隐匿传播和演化出来的。

还有一些人认为病毒可能藏身于啮齿动物或其他动物，而不是人群中，因此经历了不同的演化压力，最终筛出了一大堆见都没见过的突变。“这尼玛就是一朵奇葩”，SCRIPPS研究所的大佬Kristian Andersen老师表示，很多突变以前从来都没见过啊可以说！

“太有趣了，这货简直与众不同”，亚利桑那大学大佬Mike Worobey老师说。尽管他倾向于支持免疫抑制感染者起源论，但根据最近的某预印本，2020年11月下旬至2021年1月上旬，在爱荷华州采样的白尾鹿中有80%携带了新冠病毒。Worebey老师说： “因此这让我很好奇，其他物种是否会发生长期感染？随着时间的推移，这确实有可能提供足够的选择压力。”

It’s too early to rule out any theory about Omicron’s origin, says Aris Katzourakis, an evolutionary biologist at the University of Oxford, but he is skeptical of the animal scenario, given the sheer number of human infections. “I’d start worrying about animal reservoirs more if we were succeeding in suppressing the virus, and then I could see it as somewhere it might hide.”

Many global health leaders have used the emergence of Omicron to focus the world’s attention on the huge gap between COVID-19 vaccinations in richer and poorer countries. Richard Hatchett, head of the Coalition for Epidemic Preparedness Innovations, opened his remarks at the World Health Assembly on 29 November by saying low vaccine coverage in South Africa and Botswana had “provided a fertile environment” for the variant’s evolution. “The global inequity that has characterized the global response has now come home to roost,” he said.

Yet there is little evidence to support that statement, some scientists say. “The idea that if we had vaccinated more in Africa, we wouldn't have this: I'd like that to be true, but we have literally no way of knowing,” Katzourakis says. For now, the lessons to be drawn from Omicron remain as unknown as its origin.

牛津大学进化生物学家Aris Katzourakis老师表示，现在排除Omicron起源三种假说的任意一种都还为时过早，但他本人不太相信跨物种回传的说法。Katzourakis老师说：“等到咱成功控制人类的大流行之后，再慢慢操心动物宿主的问题也不迟是吧~”。

许多国际健康领域大佬都利用Omicron的出现来试图提醒全世界关注发达国家和发展中国家在疫苗分配方面的巨大差距。比如CEPI负责人Richard Hatchett老师在11月29在世界卫生大会上发表讲话时就提到“南非和博茨瓦纳的疫苗覆盖率低为该变种的演化【提供了肥沃的环境】”。他说：“本次大流行的全球应对措施，最大的特点就是不公平，而这一点已然根深蒂固了。”

然而一些科学家表示Hatchett老师的说法缺乏证据支持。Katzourakis老师说：“如果我们在非洲接种更多疫苗，Omicron就不会出现——我倒是希望这是真的，但这一点根本没法实锤”。

目前，我们到底要从Omicron的诞生当中吸取啥教训？这一点就如同它的起源一样纯属未知数。