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科學家利用加速演化法產生防禦神經毒氣的酵素

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Protection against nerve gas attack is a significant component of the defense system of many countries around the world. Nerve gases are used by armies and terrorist organizations, and constitute a threat to both the military and civilian populations, but existing drug solutions against them have limited efficiency.

防禦神經毒氣攻擊是全球諸多國家防禦體系的重要一環。神經毒氣被軍隊及恐怖組織所使用,因此對軍人及平民皆構成威脅。不過,現有對付神經毒氣的藥物解決方案,效能有限。

 

A multidisciplinary team of scientists at the Weizmann Institute of Science succeeded in developing an enzyme that breaks down such organophosphorus nerve agents efficiently before damage to nerves and muscles is caused. Their results have recently been published in the journal Nature Chemical Biology.

一支以色列魏茲曼科學研究所的多學科科學家團隊成功研發一種,在有機磷神經毒劑對神經及肌肉造成損傷前,有效將其分解的酵素。他們的研發結果,最近(2011)已經發表於《自然•化學生物學》期刊。

 

Recent experiments performed in a U.S. military laboratory (USAMRICD) have shown that injecting a relatively small amount of this enzyme into animals provides protection against certain types of nerve agents, for which current treatments show limited efficacy.

最近(2011)於美國軍事實驗室(USAMRICDUnited States Army Medical Research Institute of Chemical Defense,美國陸軍化學防禦醫學研究所)進行的諸多實驗已經證實,將相當少量的上述酵素注入動物中,提供了對當前療法展示有限效能之某些類型神經毒劑的保護作用。

 

Nerve agents disrupt the chemical messages sent between nerve and muscle cells, causing loss of muscle control, and ultimately leading to death by suffocation. Nerve agents interfere with the activity of acetylcholinesterase, the enzyme responsible for the breakdown of the chemical messenger – acetylcholine. As a result, acetylcholine continues to exert its effect, resulting in constant muscle contraction throughout the body.

神經毒劑會擾亂神經與肌肉細胞間傳遞的化學信息,造成肌肉失去控制,而最終導致窒息死亡。神經毒劑會干擾乙酰膽鹼酯酶的活性,這是負責分解化學信使(乙酰膽鹼)的酵素。結果,乙酰膽鹼持續發揮效應,導致全身肌肉不斷攣縮。

 

Several drugs exist that are used to treat cases of nerve agent poisoning. Although these drugs are somewhat effective when exposed to small doses of the nerve agent, they do not provide protection against high-dose exposure; they are not effective against all types of nerve agents; or they cause serious side effects. Neither are they able to prevent nor repair cerebral and motor nerve damage caused by the nerve agent.

實際上有若干藥物被用來治療神經毒劑中毒的病例。雖然曝露於小劑量的神經毒劑時,此些藥物有點療效,不過高劑量曝露時,無法提供保護作用。此些藥物並非對所有類型神經毒劑皆有效,且會引發嚴重副作用。它們既無法預防也無法修復,因神經毒劑造成之大腦及運動神經的損傷。

 

An ideal solution to the problem is to use enzymes – proteins that speed up chemical reactions – to capture and break down the nerve agent before it gets the chance to bind to the acetylcholinesterase, thereby preventing damage. The main obstacle facing the realization of this idea, however, is that nerve agents are man-made materials and therefore, evolution has not developed natural enzymes that are able to carry out this task. 

上述問題的理想解決方法,是在神經毒劑獲得與乙酰膽鹼酯酶結合機會之前,使用加速化學反應的酵素來逮住它並加以分解,從而防止損傷。不過,此構想面臨的主要實現障礙,神經毒劑是種人造物質,因此演化尚未發展出,能執行此任務的天然酵素。

 

Scientists worldwide have previously succeeded in identifying enzymes that are able to break down similar materials, but these enzymes were characterized by low efficiency. Large amounts of the enzyme were therefore required in order to break down the nerve agent, rendering their use impractical.

先前,全球諸多科學家已經成功確認,諸多能分解類似物質的酵素。不過,此些酵素的缺點是效能很低。因此,為了分解神經毒劑,需要大量的該種酵素,這造成使用上變得不切實際。

 

This is where Prof. Dan Tawfik of the Weizmann Institute’s Biological Chemistry Department enters the picture. Tawfik's group developed a special method to artificially induce “natural selection” of enzymes in a test tube, enabling them to engineer “tailor-made” enzymes.

這是魏茲曼科學研究所生物化學系教授,Dan Tawfik感興趣的所在。Tawfik的團隊研發了一種,在試管中,人工誘發自然選擇酵素的特殊方法。這使得他們能設計量身訂製的酵素。

 

The method is based on introducing many mutations to an enzyme, and scanning the variety of mutated versions that were created in order to identify those that exhibit improved efficiency. These improved enzymes then repeatedly undergo further rounds of mutations and selection for higher efficiency. In previous studies, Tawfik showed that this method can improve the efficiency of enzymes by factors of hundreds and even thousands.

上述方法是以將諸多突變體導入酵素中為基礎,然後掃描此些不同的突變體,以便確認哪些展現經改善的效能。之後為了更高的效能,此些經改善的酵素進一步重複經受多次突變與淘汰。在先前諸多研究中,Tawfik證實,藉由數百甚至數千遺傳因子,此方法能改善酵素的效能。

 

For the current task, Tawfik selected an enzyme that has been extensively studied in his laboratory, known as PON1. The main role of this enzyme, found naturally in the human body, is to break down the products of oxidized fats that accumulate on blood vessel walls, thus preventing atherosclerosis. But PON1 seems to be a bit of a “moonlighter” as it has also been found to degrade compounds belonging to the family of nerve agents.

為了當前的研究工作,Tawfik選擇了一種,在實驗室中,已經廣泛被研究,被通稱為PON1的酵素。該於人體中,被自然發現的酵素,主要角色是分解積聚於血管壁上,經氧化的脂肪產物,因此防止動脈粥樣硬化症。不過,PON1似乎也有點是兼差者,因為也曾被發現降解屬於神經毒劑族的化合物。

 

However, because this activity has not fully evolved and developed through natural selection, its efficiency in carrying out the task remains very low. But by using the directed evolution method, scientists hope that they will be able to evolve this random “moonlighting” activity into PON1’s main “day job,” which would be carried out more quickly and efficiently than before.

然而,由於該活性不曾透過自然淘汰,而徹底演化及發展過。因此,執行上述工作上的效能依然很低。不過,藉由引導的演化方法,科學家們期盼能將此隨機兼差的活性,演化進入比先前更快速且更有效能被執行之PON1的主要白天工作

 

In the first phase, Tawfik and his team, including research fellow Dr. Moshe Goldsmith and postdoctoral student Dr. Rinkoo Devi Gupta, induced a number of mutations in PON1 – some random and others directed at key sites on the enzyme. To identify the most effective PON1 mutants, the scientists joined forces with Yacov Ashani of the Structural Biology Department.

在第一階段,Tawfik及其包括研究員Moshe Goldsmith博士,及博士後學生Rinkoo Devi Gupta博士的團隊在PON1中,有些隨機及其他針對該酵素關鍵處所,誘發諸多突變。為了確認最有效能的PON1突變體,此些科學家與結構生物系的Yacov Ashani進行合作。

 

The method that the scientists developed closely mimics what happens in the body upon exposure to nerve agents: They put the acetylcholinesterase in a test tube together with a specific mutant PON1 enzyme that they wanted to test, and added a small amount of nerve agent to it.

此些科學家研發的方法,徹底模仿了曝露於神經毒劑時,人體中所發生的事:他們將乙酰膽鹼酯酶及想測試的特定突變型PON1酵素一起置於試管中,而後添加少量的神經毒劑。

 

In cases where the acetylcholinesterase continued to function properly, it could be concluded that PON1 rapidly degraded the nerve agent before it was able to cause damage to the acetylcholinesterase.

在諸多事例中,乙酰膽鹼酯酶持續適當起作用,因此能斷言,在神經毒劑能對乙酰膽鹼酯酶造成損傷前,PON1已迅速降解了神經毒劑。

 

After several rounds of scanning, the scientists succeeded in indentifying active mutant enzymes, which are able to break down the nerve agents soman and cyclosarin effectively before any damage is caused to the acetylcholinesterase. These mutant enzymes have been structurally analyzed by a team of scientists from the Structural Biology Department, which included Profs. Joel Sussman and Israel Silman, and research student Moshe Ben-David.

在多次篩選之後,此些科學家成功確認了諸多具活性的突變酵素,此些酵素在索曼(soman:甲氟磷酸異己脂)及環沙林(cyclosarin:甲氟磷酸異丙脂)等神經毒劑,對乙酰膽鹼酯酶造成任何損傷前,能有效加以分解。

 

These mutant enzymes have been structurally analyzed by a team of scientists from the Structural Biology Department, which included Profs. Joel Sussman and Israel Silman, and research student Moshe Ben-David.

一支來自結構生物系的科學家團隊(包括Joel SussmanIsrael Silman教授及研究生Moshe Ben-David)已經進行了,此些突變酵素的結構分析。

 

Further experiments have shown that when these enzymes were given as a preventative treatment before exposure, they afforded animals near-complete protection against these two types of nerve agents, even when exposed to relatively high levels.

諸多進一步的實驗業已證實,在曝露於上述兩種神經毒劑之前,此些酵素被施予作為預防性治療。甚至當曝露於極高劑量時,也能為動物提供近乎完全的防護作用。

 

The scientists plan to further expand the scope and develop preventive treatment that provides protection against all types of existing nerve agents. They are also trying to develop enzymes with high enough efficiency to be able to very rapidly break down the nerve agent so they could be used to prevent the lethal effects of nerve agents by injection immediately after exposure.

此些科學家計劃進一步擴大範圍,並研發能提供防禦現有各類型神經毒劑的預防性療法。目前,他們也試圖研發具有,能極迅速分解神經毒劑的高效能酵素。以便在曝露後,能藉由立即注射,來防止神經毒劑的致命後果。

 

 

原文網址:https://wis-wander.weizmann.ac.il/life-sciences/weizmann-institute-scientists-used-accelerated-evolution-develop-enzymes-provide

翻譯:許東榮

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