CGG-CGG，不可能在自然界存的基因信標，在武漢肺炎病毒中出現

 The Science Suggests a Wuhan Lab Leak    WSJ 20210606

The Covid-19 pathogen has a genetic footprint that has never been observed in a natural coronavirus.

The possibility that the pandemic began with an escape from the Wuhan Institute of Virology is attracting fresh attention. President Biden has asked the national intelligence community to redouble efforts to investigate.

Much of the public discussion has focused on circumstantial evidence: mysterious illnesses in late 2019; the lab’s work intentionally supercharging viruses to increase lethality (known as “gain of function” research). The Chinese Communist Party has been reluctant to release relevant information. Reports based on U.S. intelligence have suggested the lab collaborated on projects with the Chinese military.

But the most compelling reason to favor the lab leak hypothesis is firmly based in science. In particular, consider the genetic fingerprint of CoV-2, the novel coronavirus responsible for the disease Covid-19.

In gain-of-function research, a microbiologist can increase the lethality of a coronavirus enormously by splicing a special sequence into its genome at a prime location. Doing this leaves no trace of manipulation. But it alters the virus spike protein, rendering it easier for the virus to inject genetic material into the victim cell. Since 1992 there have been at least 11 separate experiments adding a special sequence to the same location. The end result has always been supercharged viruses.

A genome is a blueprint for the factory of a cell to make proteins. The language is made up of three-letter “words,” 64 in total, that represent the 20 different amino acids. For example, there are six different words for the amino acid arginine, the one that is often used in supercharging viruses. Every cell has a different preference for which word it likes to use most.

In the case of the gain-of-function supercharge, other sequences could have been spliced into this same site. Instead of a CGG-CGG (known as “double CGG”) that tells the protein factory to make two arginine amino acids in a row, you’ll obtain equal lethality by splicing any one of 35 of the other two-word combinations for double arginine. If the insertion takes place naturally, say through recombination, then one of those 35 other sequences is far more likely to appear; CGG is rarely used in the class of coronaviruses that can recombine with CoV-2.

In fact, in the entire class of coronaviruses that includes CoV-2, the CGG-CGG combination has never been found naturally. That means the common method of viruses picking up new skills, called recombination, cannot operate here. A virus simply cannot pick up a sequence from another virus if that sequence isn’t present in any other virus. 事實上，在包括CoV-2在內的整個冠狀病毒類別中，CGG-CGG組合從未被自然發現過。這意味著病毒獲得新技能的常見方法，即重組，在這裡不能發揮作用。如果一個病毒的序列不存在於任何其他病毒中，那麼它就不能從另一個病毒中獲得該序列。

Although the double CGG is suppressed naturally, the opposite is true in laboratory work. The insertion sequence of choice is the double CGG. That’s because it is readily available and convenient, and scientists have a great deal of experience inserting it. An additional advantage of the double CGG sequence compared with the other 35 possible choices: It creates a useful beacon that permits the scientists to track the insertion in the laboratory. 儘管雙CGG被自然抑制，但在實驗室工作中情況正好相反。選擇的插入序列是雙CGG。這是因為它很容易獲得和方便，而且科學家們有大量的插入經驗。與其他35種可能的選擇相比，雙CGG序列還有一個優勢。它創造了一個有用的信標，使科學家能夠在實驗室中跟蹤插入的情況。

Now the damning fact. It was this exact sequence that appears in CoV-2. Proponents of zoonotic origin must explain why the novel coronavirus, when it mutated or recombined, happened to pick its least favorite combination, the double CGG. Why did it replicate the choice the lab’s gain-of-function researchers would have made? 現在是確定的事實。正是這個確切的序列出現在 CoV-2 中。支持這是人畜共通病的人必須解釋：為什麼新型冠狀病毒在發生突變或重組時，碰巧選擇了它最不喜歡的組合，即雙 CGG。為什麼它複製了實驗室的「功能獲得」研究人員會做出的選擇？

Yes, it could have happened randomly, through mutations. But do you believe that? At the minimum, this fact—that the coronavirus, with all its random possibilities, took the rare and unnatural combination used by human researchers—implies that the leading theory for the origin of the coronavirus must be laboratory escape. 是的，它可能是隨機發生的，通過突變。但你相信這一點嗎？至少，這個事實--冠狀病毒，以其所有的隨機可能性，採取了人類研究人員使用的罕見的非自然組合--暗示著冠狀病毒起源的主要理論必須是實驗室逃逸。

When the lab’s Shi Zhengli and colleagues published a paper in February 2020 with the virus’s partial genome, they omitted any mention of the special sequence that supercharges the virus or the rare double CGG section. Yet the fingerprint is easily identified in the data that accompanied the paper. Was it omitted in the hope that nobody would notice this evidence of the gain-of-function origin?

But in a matter of weeks virologists Bruno Coutard and colleagues published their discovery of the sequence in CoV-2 and its novel supercharged site. Double CGG is there; you only have to look. They comment in their paper that the protein that held it “may provide a gain-of-function” capability to the virus, “for efficient spreading” to humans. 雙重CGG就在那裡；你只需要看一下。他們在論文中評論說，持有它的蛋白質「可能為病毒提供一種功能增益」的能力，「以便有效地傳播」到人類。

There is additional scientific evidence that points to CoV-2’s gain-of-function origin. The most compelling is the dramatic differences in the genetic diversity of CoV-2, compared with the coronaviruses responsible for SARS and MERS.  最引人注目的是CoV-2的遺傳多樣性與造成SARS和MERS的冠狀病毒相比有巨大的差異。

Both of those were confirmed to have a natural origin; the viruses evolved rapidly as they spread through the human population, until the most contagious forms dominated. Covid-19 didn’t work that way. It appeared in humans already adapted into an extremely contagious version. No serious viral “improvement” took place until a minor variation occurred many months later in England.

這兩種病毒都被證實具有自然起源；這些病毒在人類群體中傳播時迅速進化，直到最具傳染性的形式佔據主導地位。Covid-19並不是這樣的。它出現在人類身上時，已經適應了一個極具傳染性的版本。沒有發生嚴重的病毒"改進"，直到許多月後在英國發生了一個小的變異。

Such early optimization is unprecedented, and it suggests a long period of adaptation that predated its public spread. Science knows of only one way that could be achieved: simulated natural evolution, growing the virus on human cells until the optimum is achieved. That is precisely what is done in gain-of-function research. Mice that are genetically modified to have the same coronavirus receptor as humans, called “humanized mice,” are repeatedly exposed to the virus to encourage adaptation. 這樣的早期優化是史無前例的，它表明在其公開傳播之前有一個漫長的適應期。科學界只知道有一種方法可以實現：類比自然進化，在人類細胞上培育病毒，直到達到最佳狀態。這正是功能增益研究中的做法。經過基因改造的小鼠具有與人類相同的冠狀病毒受體，稱為「人源化小鼠」，它們被反覆暴露在病毒中以鼓勵適應。

The presence of the double CGG sequence is strong evidence of gene splicing, and the absence of diversity in the public outbreak suggests gain-of-function acceleration. The scientific evidence points to the conclusion that the virus was developed in a laboratory. 雙CGG序列的存在是基因拼接的有力證據，而公共爆發中缺乏多樣性表明功能增益的加速。科學證據表明，該病毒是在實驗室中開發的。

Dr. Quay is founder of Atossa Therapeutics and author of “Stay Safe: A Physician’s Guide to Survive Coronavirus.” Mr. Muller is an emeritus professor of physics at the University of California Berkeley and a former senior scientist at the Lawrence Berkeley National Laboratory.