科學家正在學習改寫生命密碼（2/2）

Recently the New York Times reported the following:

Scientists Are Learning to Rewrite the Code of Life (2/2)

In a giant feat of genetic engineering, scientists have created bacteria that make proteins in a radically different way than all natural species do.

NYT - By Carl Zimmer -Origins- (Carl Zimmer covers news about science for The Times and writes the Origins column.)

July 31, 2025

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In 2019, the Medical Research Council team unveiled their first successful creation: a version of E. coli with only 61 codons, which they named Syn61. Its ability to survive without three codons encouraged them to whittle its genetic code down even further.

“We were motivated to see how far we could streamline the genetic code,” Dr. Robertson said.

He and his colleagues set out to create Syn57, a version of E. coli with only 57 codons. They entered a race with Dr. Nyerges and his colleagues at Harvard, who were already trying to reach that same goal.

For Syn61, the researchers had altered more than 18,000 codons in E. coli’s genome. To make Syn57, they would have to alter more than 100,000. They tested these changes by making small fragments of DNA and observing how well the microbe could read them.

Some changes caused no trouble, but others caused devastating harm. Bacteria have certain genes that overlap, for instance, and changing a codon in one can accidentally wreck the sequence of the other.

The scientists had to invent a lot of repairs to undo the damage, including separating overlapping pairs of genes to create two distinct stretches of DNA.

“We definitely went through these periods where we were like, ‘Well, will this be a dead end, or can we see this through?’” Dr. Robertson recalled.

Glitch by glitch, the researchers figured out how to fix the altered DNA. On Thursday, the researchers announced that they had succeeded: They had created Syn57.

“It’s kind of crazy that they were able to pull this off,” said Yonatan Chemla, a synthetic biologist at M.I.T. who was not involved in the study. “It’s a technically demanding tour de force.”

Meanwhile, at Harvard, Dr. Nyerges and his colleagues have encountered glitches of their own. “There’s a lot more in genomes than we thought,” he said. “We are still not great at designing biology.”

Last month, his team reported that they had assembled a 57-codon genome into seven pieces of DNA. They are now working on stitching them together into a single molecule. “We will definitely get there,” he said.

Syn57 is unquestionably alive, but just barely. E. coli typically takes an hour to double its population; Syn57 needs four hours. “It’s extremely feeble,” Dr. Chemla said.

Dr. Robertson and his colleagues are now tinkering with Syn57 to see if they can speed up its growth. If they succeed, other scientists might be able to engineer it to carry out useful jobs that ordinary microbes can’t.

Along with the 20 amino acids that our cells use to make proteins, chemists can create hundreds of others. It might be possible to reprogram Syn57 so that its seven missing codons encode unnatural amino acids. That would enable bacteria to make new kinds of drugs or other useful molecules.

Syn57 might also help scientists address the potential risks that could come if engineered microbes were released into the environment. Microbiologists have long investigated how microbes might eat plastic or detect pollutants in the ground. But bacteria trade genes with ease; a gene could escape from an engineered microbe and spread through the environment, potentially causing ecological harm.

Then again, that spread would become a threat only if other bacteria could read the engineered gene and make proteins from it. If the gene came from a microbe like Syn57, which used a different genetic code, it would be gibberish to natural microbes.

“We can then prevent the escape of information from our synthetic organism,” Dr. Robertson said.

Organisms like Syn57 are also allowing scientists to tackle the puzzle of the genetic code. In 1968, the Nobel-prize winning biologist Francis Crick sketched out two opposing hypotheses for why it is both redundant and universal.

One possibility was that the 64-codon genetic code had some hidden advantage over any other arrangement. When it evolved on the early Earth, natural selection favored it until it had outcompeted all others.

But Crick leaned toward a second explanation: The genetic code was largely the result of chance. He speculated that mutations caused certain codons to encode certain amino acids. As early life-forms expanded their genetic code, they could build more complex proteins. But evolution connected codons to amino acids at random.

Once the proteins became big and complex, the genetic code could evolve no further; any mutation that might change it would produce a lot of defective proteins. Crick called this scenario a “frozen accident.”

Dr. Robertson said that the ability of Syn57 to survive without seven codons led him to favor Crick’s frozen-accident theory. “This reveals that there is nothing fundamental about the universal genetic code,” he said.

Translation

科學家正在學習改寫生命密碼（2/2）

在基因工程的一項偉大壯舉中，科學家們創造了一種與所有自然物種截然不同的蛋白質合成方式的細菌

（繼續）

2019年，醫學研究委員會團隊公佈了他們的第一個成功創造：一種只有61個密碼子的大腸桿菌，他們將其命名為Syn61。它能夠在欠缺三個密碼子的情況下存活，這促使團隊進一步精簡其遺傳密碼。

Robertson博士說: 「我們很想知道我們可將遺傳密碼精簡到什麼程度」。

他和他的同事著手創造Syn57，一種只有57個密碼子的大腸桿菌。他們與哈佛大學的 Nyerges博士及其同事展開了一場競賽，後者也已經在努力實現同樣的目標。

為了合成 Syn61，研究人員改變了大腸桿菌基因組中超過 18,000 個密碼子。而為了合成 Syn57，他們則需要改變超過 10 萬個密碼子。他們透過製作小片段 DNA 並觀察微生物讀取這些密碼子的能力來測試這些改變。

有些改變沒有造成任何問題，但有些改變卻造成了毀滅性的傷害。例如，細菌中某些基因是重疊的，改變其中一個基因的密碼子可能會意外地破壞另一個基因的序列。

科學家必須發明許多修復方法來修理這些損傷，包括分離重疊的基因對，產生兩條不同的 DNA 片段。

Robertson博士回憶道:「我們確實經歷過這樣的時期 - 例如問『哎,這會是一條死路嗎，我們能堅持下去？』」

研究人員透過一個又一個的嘗試，找到了修理被改變的 DNA 的方法。週四，研究人員宣佈他們成功了：他們合成了 Syn57。

並未參與這項研究的麻省理工學院的合成生物學家 Yonatan Chemla 說道: 「他們能做到這一點真是太不可思議了」;「這真是一項技術要求極高的傑作」。

同時，在哈佛大學，Nyerges 博士和他的同事們也遇到了一些小問題。他說: 「基因組比我們想像的要多得多」; 「我們在設計生物學方面仍然不夠出色」。

上個月，他的團隊報告稱，他們已將一個包含57個密碼子的基因組組裝成七個DNA片段。現在他們正致力於將它們拼接成一個單分子。 他說: 「我們一定會成功」。

Syn57無疑是活着的，但只是勉強存活。大腸桿菌通常需要一個小時才能使其數量翻倍，而Syn57則需要四個小時。 Chemla博士說: 「它是非常脆弱」。

Robertson 博士和他的同事目前正在對Syn57進行改進，看看能否加快其生長速度。如果他們成功了，其他科學家或許能夠改造它，使其執行普通微生物無法做出的有用功能。

連同我們細胞用來製造蛋白質的20種氨基酸，化學家還可以創造數百種其他氨基酸。或許可以對Syn57進行重新編程，使缺少了的七個密碼子編碼出非天然胺基酸。這將使細菌能夠製造新型藥物或其他有用分子。

Syn57 或許也能幫助科學家應對被工程微生物所釋放到環境中而可能帶來的潛在風險。微生物學家長期以來一直在研究微生物如何消化塑膠或檢測地下污染物。但細菌很容易交換基因；基因可以從工程微生物中逸出，並在環境中傳播，可能造成危害生態。

然而，只有當其他細菌能夠讀取工程基因, 並利用其製造蛋白質時，這種傳播才會構成威脅。如果基因來自像Syn57這樣使用不同遺傳密碼的微生物，那麼它對天然微生物來說就如同亂碼一樣。

羅伯森博士說: 「這樣我們就可以防止密碼資訊從我們的合成生物體中洩露」。

像 Syn57 這樣的生物也讓科學家得以破解遺傳密碼之謎。 1968 年，諾貝爾獎得主、生物學家Francis Crick 提出了兩種截然相反的假設，以解釋為何遺傳密碼既冗餘又普遍。

一種可能性是，64 個密碼子的遺傳密碼比其他任何排列方式都具有某種隱藏的優勢。當它在早期地球上進化時，自然選擇青睞它，直到它超越了所有其他排列方式。

但 Crick 傾向於第二種解釋：遺傳密碼很大程度上是偶然的。他推測突變導致某些密碼子編碼出某些胺基酸。隨著早期生命形式擴展其遺傳密碼，它們可以建立更複雜的蛋白質。但生命進化把密碼子與胺基酸隨機地連結。

一旦蛋白質變得龐大而複雜，遺傳密碼就無法進一步進化；任何可能改變它的突變都會產生大量有缺陷的蛋白質。Crick將這種情況稱為「凍結意外」。

Robertson博士表示，Syn57 能夠在沒有 7 個密碼子的情況下存活下來，這讓他更傾向於Crick的「凍結意外」理論。他說: 「這表明通用遺傳密碼並沒有什麼基本性的」。

       So, over the past decade, scientists have built microbes with smaller codes. A new study describes a microbe with the most streamlined genetic code yet that has seven missing codons. Scientists believe that it would enable engineered bacteria to make new kinds of drugs or other useful molecules. Apparently, our ability to rewrite the code of life will eventually change our world.

Note:

1. A "frozen accident" (凍結意外)is a phenomenon where an event or decision that happened by chance becomes permanent and unchangeable due to its deep integration into a complex system, making any future alteration too disruptive or impossible. The term was notably used by Francis Crick to describe the genetic code, suggesting it was an arbitrary, early evolutionary development that became "frozen" because modifying it now would require fundamentally changing the entire cellular machinery.