SARS-COV-2 is following the evolutionary rule book to perfection

2021-02-21 藍海航線BO

Covid-19

 

Variations on a theme

SARS-COV-2 is following the evolutionary rule book to perfection

圍繞一個主題產生的不同變種

新冠病毒完美的遵循了進化法則

【經濟學人 2021.1.2期】

 

Natural selection is a powerful force. In circumstances that are still disputed, it took a bat coronavirus and adapted it to people instead. The result has spread around the globe. Now, in two independent but coincidental events, it has modified that virus still further, creating new variants which are displacing the original versions. It looks possible that one or other of these novel viruses will itself soon become a dominant form of SARS-COV-2。

自然選擇是一種強大的力量,自然選擇利用蝙蝠身上的病毒,將其改造並讓它適應了人類 。由此一來,現在病毒蔓延了整個世界。而現在,在兩個彼此獨立但非常巧合的事件中,自然選擇進一步對其進行了修改,從而創造出了兩個新的變種來取代過去原有的版本。現在看來,這兩個新變異出來的病毒中,其中的某一種會很快成為新冠病毒的主要形式。

 

Knowledge of both became widespread in mid-December. In Britain, a set of re-searchers called the Covid-19 Genomics UK Consortium (COG-UK) published the genetic sequence of variant b.1.1.7, and NERVTAG,a group that studies emerging viral threats, advised the government that this version of the virus was 67-75% more transmissible than those already circulating in the country. In South Africa, meanwhile, Salim Abdool Kalim, a leading epidemiologist, briefed the country on all three television channels about a variant called 501.v2 which, by then, was accounting for almost 90% of new covid-19 infections in the province of Western Cape.

關於這兩個變種病毒的知識是從去年12月中旬的時候就已經開始廣泛流傳了。在英國有一個簡稱COG-UK的組織裡的研究人員公布了病毒變種B117的基因序列,然後專門研究新出現病毒對人類構成威脅的機構叫NERVTAG。這家機構向政府提出建議說,這種病毒變體的傳染性比現在英國正在流行的病毒的傳染性要高出67-75%。在南非,有個著名的流行病學家,在三個電視屏道上介紹了一種名為501.V2的變體。他在宣布的時候,這個變種已經佔南非西開普省新冠感染病例的近90%。

 

Britain responded on December 19th, by tightening restrictions already in place. South Africa’s response came on December 28th, in the wake of its millionth recorded case of the illness, with measures that extended a night-time curfew by two hours and reimposed a ban on the sale of alcohol. Other countries have reacted by discouraging even more forcefully than before any travel between themselves and Britain and South Africa. At least in the case of b.1.1.7, though, this has merely shut the stable door after the horse has bolted. That variant has now been detected in a score of countries besides Britain--and from these new sites, or from Britain, it will spread still further. Isolated cases of 501.v2 outside South Africa have been reported, too, from Australia, Britain, Japan and Switzerland.

英國在12月19日的時候做出了回應,加緊了已經實施的限制措施。南非12月28日,在第100萬個病例出現之後,才宣布採取新的措施。將宵禁的時間延長兩個小時,並重新實施了對酒精的銷售禁令。其他的國家比以往更加強烈的阻止了去英國和南非的旅行。但是英國的B117的病毒案例來說,相當於是馬跑了之後才把馬廄關上,因為病毒已經出了國門。現在,在英國之外,這種病毒變種已經在20個國家被檢測出來,而且從這些新的地點或者英國,這種變種還會進一步的傳播。在南非以外的澳大利亞,英國日本和瑞士也分別報告了在當地發現南非的501.V2的變種。而且感染案例彼此之間是孤立的。

 

So far, the evidence suggests that despite their extra transmissibility, neither new variant is more dangerous on a case- by-case basis than existing versions of the virus. In this, both are travelling the path predicted by evolutionary biologists to lead to long-term success for a new pathogen―which is to become more contagious (which increases the chance of onward transmission) rather than more deadly (which reduces it). And the speed with which they have spread is impressive.

到現在為止,雖然有證據表明說,這種新的變種有更強大的傳播力。但是就具體病例而言這兩種變異病毒不會比現在的主流病毒更危險。從這一點來看,這兩種病毒的變種都是沿著進化生物學家預測出來的路在走。病毒的目標就是希望這種病原體獲得長期的成功。它要使自己變得有更強的傳染性,從而增加傳播的機會,而不是變得更致命,因為致命會減少它自己傳播的機會。這些病體的傳播速度是很驚人的。

 

The first sample of B.1.1.7 was collected on September 20th, to the south-east of London. The second was found the following day in London itself. A few weeks later, at the beginning of November, B.1.1.7 accounted for 28% of new infections in London. By the first week of December that had risen to 62%. It is probably now above 90%.

第一個B117的變種是在9月20日在倫敦的東南部採集到的,第二個樣本是隨後的第二天在倫敦本地採集到的。幾周之後,11月初時B117佔到英國新感染病毒病例的28%。到12月第1周的時候上升至62%,而現在可能佔到90%。

 

Variant 501.v2 has a similar history. It began in the Eastern Cape, the first samples dating from mid-October, and has since spread to other coastal provinces.

501.V2也有很相似的歷史,一開始是從東開普省,十月中旬發現第一批樣本,從那時起就蔓延了其他的南非省份。

 

The rapid rise of b.1.1.7 and 501.v2 raises several questions. One is why these particular variants have been so successful. A second is what circumstances they arose in. A third is whether they will resist any of the new vaccines in which such store is now being placed.

B117和501.V2這兩種病毒的快速發展,讓人們提出幾個問題。1為什麼它們會如此的成功?2這些變異是在什麼樣的環境下出現的。3這種變異病毒已經佔據新發病毒如此高的比例,疫苗還有效嗎?

 

The answers to the first of these questions lie in the variants』 genomes. COG-UK’s investigation of B.1.1.7 shows that it differs meaningfully from the original version of SARS-COV-2 in 17 places. That is a lot. Moreover, several of these differences are in the gene for spike, the protein by which coronaviruses attach themselves to their cellular prey. Three of the spike mutations particularly caught the researchers』eyes.

第一個問題的答案就在病毒的基因組裡,COG-UK對B117的調查顯示,這種新的病毒的變體是有17個地方和新冠存在有意義的差異。有幾個變異是存在刺突蛋白的基因裡,而新冠病毒正是通過刺突來附著到它們的獵物上的。其中有三種突變尤其引起了研究者的注意。

 

One, n501y, affects the 501st link in spike’s amino-acid chain. This link is part of a structure called the receptor-binding domain, which stretches from links 319 to 541. It is one of six key contact points that help lock spike onto its target, a protein called ACE2 which occurs on the surface membranes of certain cells lining the airways of the lungs. The letters in the mutation’s name refer to the replacement of an amino acid called asparagine (「n」, in biological shorthand) by one called tyrosine (「y」). That matters because previous laboratory work has shown that the change in chemical properties which this substitution causes binds the two proteins together more tightly than normal. Perhaps tellingly, this particular mutation (though no other) is shared with 501.v2.

其中有個叫N501Y影響到刺突蛋白胺基酸鏈的第501個鏈上。這個鏈是受體結合的一部分,這個結構是從319號延伸到541號,這個結構是幫助刺突蛋白鎖定獵物的6個關鍵接觸點之一。這種目標獵物就是叫ACE2的蛋白質,它長在人類肺呼吸道的表層膜上。叫作N的胺基酸被叫作Y的胺基酸所取代。這點也很重要,因為之前的實驗室研究發現,這種替代所以引起的化學發應性質的變化會使病毒上的刺突蛋白和人類呼吸道中ACE2連接的更加緊密。很能說明問題的一點是,這種特殊的突變在南非的501.V2上同時出現。

 

Golden spike


B.1.1.7’s other two intriguing spike mutations are 69-70del, which knocks two amino acids out of the chain altogether, and P681H. which substitutes yet another amino acid, histidine, for one called proline at chain-link 681. The double-deletion attracted the researchers』 attention for several reasons, not the least being that it was also found in a viral variant which afflicted some farmed mink in Denmark in November, causing worries about an animal reservoir of the disease developing. The substitution is reckoned significant because it is at one end of a part of the protein called the s1/s2 furin-cleavage site (links 681-688), which helps activate spike in preparation for its encounter with the target cell. This site is absent from the spike proteins of related coronaviruses, such as the original SARS, and may be one reason why SARS-COV-2 is so infective.

英國的兩種變體有另外兩個很有意思的突變,一個叫69-70del,將兩個胺基酸完全從鏈上消除。另外一個叫P681H,它是用另外一種胺基酸-組氨酸來取代618號鏈上的脯氨酸。其中雙重消除的突變引起了研究者的注意。一方面在11月發現在丹麥養殖的水貂中也發現了這種病毒變體。這就引起了人們的擔心,因為這種病毒在動物群體裡會形成積累。研究人員也認為,突變過程中胺基酸的替代很重要,因為它的位置-furin-cleavage site,這個位置是有助於激活刺突蛋白,讓刺突蛋白與目標細胞的相遇做好準備。相比之下,像是SARS病毒等相關的病毒裡刺突蛋白的位置是沒有這個位點的。所以,這也可能是新冠傳染性如此強的原因。

 

 

The South African variant, 501.v2, has only three meaningful mutations, and all are in spike’s receptor-binding domain. Besides n501y, they are K417N and E

E484K (K and E are amino acids called lysine and glutamic acid). These two other links are now the subject of intense scrutiny.

南非的501.V2隻有3個有意義的突變,三個都在刺突蛋白的受體結合區域。除了N501Y還有兩個一個叫K417N,另一個叫E484K,(K和E也是兩種胺基酸的簡寫)。現在研究人員正就此進行研究。

 

Even three meaningful mutations is quite a lot for a variant to have. Just one would be more usual. The 17 found in B.1.1.7 therefore constitute a huge anomaly. How this plethora of changes came together in a single virus is thus the second question which needs an answer.

3個有意義的變異對一個病毒變體來說也是非常多的。通常只有一個。B117有17個突變是一個非常異常的情況。所以這麼多的變化是如何能在一個病毒上體現出來呢?是第二個需要我們回答的問題。

 

The authors of the COG-UK paper have a suggestion. This is that, rather than being a chance accumulation of changes, B.1.1.7 might itself be the consequence of an evolutionary process -- but one that happened in a single human being rather than a population. They observe that some people develop chronic covid-19 infections because their immune systems do not work properly and so cannot clear the infection. These unfortunates, they hypothesise, may act as incubators for novel viral variants.

於是COG-UK提出一種可能性,B117並非是變化的偶然積累,可能就是進化過程的結果。但是是發生在單個個體,而不是整個群體的過程。研究者發現,有些人會患上慢性新冠感染。因為他們身上的免疫系統不能正常工作。他們提出假設,非常不幸,這些人可能成為新的病毒變種的「孵化器」。

 

The theory goes like this. At first, such a patient’s lack of natural immunity relaxes pressure on the virus, permitting the multiplication of mutations which would otherwise be culled by the immune system. However, treatment for chronic covid-19 often involves what is known as convalescent plasma. This is serum gathered from recovered covid patients, which is therefore rich in antibodies against SARS-COV-2. As a therapy, that approach frequently works. But administering such a cocktail of antibodies applies a strong selection pressure to what is now a diverse viral population in the patient’s body. This, the COG-UK researchers reckon, may result in the success of mutational combinations which would not otherwise have seen the light of day. It is possible that B.1.1.7 is one of these.

一開始,是缺乏這些天然免疫力的病人,他本身體力就允許了這些病毒的繁殖,如果有正常的免疫系統,病毒可能早就被其所淘汰。針對慢性新冠的治療手段,會使用恢復期血漿。恢復期血漿就是從康復的新冠患者身上採集的血清。作為一種治療手段,這種方法很有效。但是利用混合抗體會給病人體內的現有的多種病毒種群施加非常大的壓力。這種壓力會使這種非常罕見的以17種組合的變異體獲得進化意義上的成功。所以B117可能就是這麼出現的。

 

The answer to the third question― whether either new variant will resist the vaccines now being rolled out―is 「probably not」. It would be a long-odds coincidence if mutations which spread in the absence of a vaccine nevertheless protected the virus carrying them from the immune response raised by that vaccine.

第三個問題就是這兩種新出現的病毒變種是不是會讓新上市的疫苗無效?答案是很可能不會。在沒有疫苗的情況下傳播起來的突變,同時還能保護病毒本身不受疫苗引起的免疫反應的影響,這種情況是機率非常低的巧合。

 

This is no guarantee for the future, though. The swift emergence of these two variants shows evolution’s power. If there is a combination of mutations that can get around the immune response which a vaccine induces, then there is a fair chance that nature will find it.

但是不知道未來會怎樣,這兩種變異病毒的迅速出現,充分顯示了進化的巨大力量。如果說有一種突變的組合可以繞過疫苗引起的免疫反應,從而讓疫苗對其失效的話,那大自然可能會發現這種突變的組合。

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