Vaccines have been reliably and affordably protecting people from diseases worldwide for centuries. Until the COVID-19 pandemic, however, vaccine development was still a long and idiosyncratic process.
幾世紀以來，疫苗一直可靠且經濟實惠地保護全世界的人們，免遭疾病侵害。然而，直到2019冠狀病毒症(COVID-19：Coronavirus Disease-19)大流行病之前，疫苗開發仍然是一個，漫長且特殊的過程。
Traditionally, researchers had to tailor manufacturing processes and facilities for each vaccine candidate, and the scientific knowledge gained from one vaccine was often not directly transferable to another.
傳統上，研究人員們必須為每種候選疫苗，量身定制生產流程及設施，且從一種疫苗獲得的科學知識，通常並非可直接轉移到另一種疫苗。
But the COVID-19 mRNA vaccines brought a new approach to vaccine development that has far-reaching implications for how researchers make drugs to treat many other diseases.
不過，COVID-19 mRNA疫苗帶來了一種，對研究人員如何製造，治療許多其他疾病的藥物，具有諸多深遠意涵的新疫苗開發方法。
I am a biochemist, and my lab at UMass Chan Medical School focuses on developing better ways to use mRNA as a drug. Although there are many possibilities for what researchers can use mRNA to treat, some important limitations remain.
我是一名生物化學家，我在美國馬薩諸塞大學陳氏醫學院的實驗室，著重於開發更佳的方法，來使用mRNA作為藥物。雖然，對研究人員們所能使用mRNA進行的治療而言，有諸多可能性。不過，仍存在一些大障礙。
Better understanding how mRNA-based drugs interact with the immune system and how they are degraded in human cells can help lead to safe, durable and effective treatments for a wide range of diseases.
更深入瞭解，以mRNA為基礎的藥物，如何與免疫系統交互作用，及它們如何在人體細胞中被降解。能有助於引領出，對廣泛疾病而言，安全、持久且有效的療法。
Messenger RNA, or mRNA, is made of four building blocks denoted by the letters A, C, G and U. The sequence of letters in an mRNA molecule conveys genetic information that directs how a protein is made.
也就是mRNA的信使RNA，是由字母 A、C、G 及U表示的四種構材組成。mRNA分子中的字母(鹼基)序列，傳遞指示蛋白質如何製造的遺傳訊息。
An mRNA drug comprises two essential components: mRNA molecules, which code for desired proteins, and the lipid molecules – such as phospholipids and cholesterol – that encapsulate them. These mRNA-lipid nanoparticles, or LNPs, are tiny spheres about 100 nanometers in diameter that protect mRNA from degradation and facilitate its delivery into target cells.
mRNA藥物包含兩種基本成分：為渴望之蛋白質指定遺傳碼的mRNA分子，及諸如磷脂質及膽固醇等，封包它們的脂質分子。此些mRNA與脂質的奈米粒子，也就是LNPs是保護mRNA免於降解，及促進其遞送至標的細胞，直徑大約100奈米的微小球體。
Once inside cells, mRNA molecules instruct the cell’s machinery to produce the target protein required for a desired therapeutic effect. For example, the mRNA in the Pfizer-BioNTech and Moderna COVID-19 vaccines directs cells to produce a harmless version of the virus’ spike protein that trains the immune system to recognize and better prepare for potential infection.
一旦進入細胞內，mRNA分子指示細胞運作部分，產生渴望之治療效果所需的標的蛋白質。譬如，美國輝瑞(Pfizer)與德國生物新技術公司(BioNTech)及美國莫德納(Moderna)COVID-19疫苗中的mRNA，指示細胞產生病毒之脊突蛋白的無害版本、訓練免疫系統識別及更佳地為潛在感染做準備。
短片網址：https://youtu.be/v-NEr3KCug8
The science behind COVID-19 mRNA vaccines has been decades in the making.
2019冠狀病毒症(COVID-19：Coronavirus Disease-19)mRNA疫苗背後的科學一直發展了數十年。
From a drug development perspective, mRNA drugs offer significant advantages over traditional drugs because they are easily programmable. Hundreds of pounds of mRNA can be made from readily available DNA templates, such that producing a different mRNA drug is as simple as changing the corresponding DNA templates.
從藥物開發前景，mRNA藥物顯露出，超越傳統藥物的顯著優點。因為，它們易於可編碼指令序列。從輕易可資取得的DNA模板，能產生數百磅的mRNA。這樣，生產不同的mRNA藥物，如同改變相應的DNA模板般簡單。
More importantly, different mRNA drugs produced by the same set of methods will have similar properties. They will be delivered to the same tissues, trigger similar levels of immune responses and degrade in similar ways. This predictability significantly reduces the development risks and financial costs of developing mRNA drugs.
更重要的是，經由同一套方法生產的不同mRNA藥物，會具有相似的屬性。它們能被遞送到相同的組織，引發相似水平的免疫反應，且以相似的方式降解。這種可預測性顯著降低了，開發mRNA藥物的開發風險及財務成本。
In addition to being easy to program, mRNA drugs have several other unique properties. For example, just like the mRNAs your body naturally produces, therapeutic mRNAs have a short half-life in cells: about one day. As a result, current mRNA technology is ideal for treatments that aren’t meant to last long in the body.
除了易於編碼指令序列之外，mRNA藥物具有若干其他的獨特屬性。譬如，治療性mRNA，就如同人體自然產生的mRNA，於細胞中，有短半衰期：大約一天。因此，對諸多不被打算，於人體內維持長時間的療法而言，當前mRNA技術是種理想之物。
This is why vaccines are popular candidates for mRNA technology: They provide long-term protection against disease after brief exposure to the drug with few side effects. There are currently more than 30 mRNA vaccine candidates, not including vaccines for COVID-19, in clinical trials.
這是為何諸多疫苗是mRNA技術的普遍候選物：在短暫曝露於此種具很少副作用的藥物後，它們提供對疾病的長期保護。目前，不包括COVID-19疫苗，有多於30種mRNA疫苗候選物，處於臨床試驗中。
Another critical feature of mRNA drugs is their intrinsic ability to stimulate the immune system. This may sound paradoxical – after all, your cells already contain large amounts of mRNAs. Why would other mRNAs activate your immune system? How does your immune system distinguish between self and nonself mRNAs?
mRNA藥物的另一種關鍵性特性，是其刺激免疫系統的原本固有能耐。畢竟，這聽起來可能很矛盾。人們的細胞早已具有大量mRNA。為何其他mRNA會激活人們的免疫系統？人們的免疫系統如何區分自身與非自身的mRNA？
The first reason involves location. Therapeutic mRNAs enter cells using endosomes – sacs made of the cell’s membrane that take in materials from the cell’s environment.
第一個原因涉及位置。治療性mRNA利用胞內體(由細胞膜組成，從細胞環境中，吸入物質的囊)，進入細胞中。
Your immune system can detect mRNA in endosomes because this is usually a sign of an RNA virus infection – cellular mRNAs normally don’t enter endosomes. When your immune system labels therapeutic mRNAs as viral material, it triggers a strong inflammatory response that can lead to severe side effects.
人們的免疫系統能察覺胞內體中的mRNA，因為這通常是種RNA病毒感染的跡象。細胞的mRNA通常不會進入胞內體中。當人們的免疫系統，將治療性mRNA標記為病毒物質時，這會引發導致嚴重副作用的強烈發炎反應。
圖1. 內吞作用是細胞外物質(諸如mRNA分子)於細胞內被吞噬的過程。
Endocytosis is the process by which material outside the cell, such as mRNA molecules, is engulfed within the cell.
One solution to this problem is to modify mRNA’s building blocks – specifically, changing the U, or uridine, to its chemical cousins, pseudouridine and N1-methylpseudouridine.
此問題的一種解決方法，是修改mRNA的構材。特別是，將U(也就是尿苷)改變成其化學近似物：假尿苷及N1-甲基假尿苷。
This subtle chemical change prevents the unwanted immune response while allowing the therapeutic mRNA to direct the cell to make the protein it encodes. The 2023 Nobel Prize in physiology or medicine was awarded to the scientists who made this breakthrough discovery. Both the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines use this technique.
此細微的化學改變防止了，不需要的免疫反應，同時允許治療性mRNA指示細胞，產生其編碼的蛋白質。2023年諾貝爾生理暨醫學獎頒予了，做出該項突破性發現的科學家。輝瑞與BioNTech及莫德納COVID-19疫苗，使用了該項技術。
The second source of unwanted immune response is impurities from mRNA production. To prepare mRNA from a DNA template, scientists use a protein called RNA polymerase that tends to make a small amount of side product called double-stranded RNA.
不需要之免疫反應的第二個來源，是來自mRNA生產時的雜質。為了從一種DNA模板調製mRNA，科學家們使用一種，被稱為RNA聚合酶的蛋白質。這種蛋白質傾向產生少量，被稱為雙股RNA的副產物。
Unlike mRNA, which is single-stranded, double-stranded RNA has two chains that form a double helix. RNA viruses also form double-stranded RNA when they replicate, and exposing cells to double-stranded RNA can lead to a strong immune response.
不像單股mRNA，雙股RNA具有兩條，形成雙螺旋鏈的鏈。當RNA病毒複製時，它們也形成雙股RNA。因此，將細胞曝露於雙股RNA，會引領出強烈的免疫反應。
Removing double-stranded RNA is challenging, especially at the industrial scale. Fortuitously, for mRNA vaccines, the residual amount of double-stranded RNA can stimulate the immune system to enhance antibody responses. However, for applications other than vaccines, a cleaner RNA product is necessary to reduce side effects.
移除雙股RNA具挑戰性，特別是在工業規模上。幸運的是，就mRNA疫苗而言，殘留量的雙股RNA能刺激免疫系統，來增強抗體反應。然而，就諸多不同於疫苗的應用而言，需要更潔淨的RNA產品，以減少副作用。
Although mRNA has the potential to transform drug development for various medical purposes, careful consideration is required to identify targets that align with the technology’s strengths.
雖然，mRNA具有改變藥物開發，供各種醫療目使用的潛力。不過，需要仔細考慮，來確認與該種技術強項相符的目標。
For example, because there is currently a limit to how long mRNA can last in the body, treatments that need a protein to be present for only a short period of time to achieve a lasting therapeutic effect are ideal. One promising example in development is using mRNA that encodes CRISPR-Cas9 gene-editing proteins to knock out genes that cause specific diseases.
譬如，由於目前mRNA，能在人體內持續多長時間，有個極限點。需要一種蛋白質，僅存在短時間，來達成持久治療效果的療法，是理想之法。一種於開發中，有指望的例子是使用，編碼CRISPR(CRISPR：Clustered Regularly Interspaced Short Palindromic Repeat，群聚、規律性間隔開的短迴文結構複製)-Cas9(CRISPR associated protein 9，是一種在某些細菌對DNA病毒之免疫防禦中，起至關重要作用的蛋白質)的編輯基因之蛋白質的 mRNA，來剔除導致特定疾病的基因。
Researchers are exploring this strategy to develop a single-dose treatment for hereditary transthyretin amyloidosis, a rare genetic disease caused by the accumulation of misfolded proteins in the heart and nerves. This disease is an ideal target for mRNA-based CRISPR gene therapy because the target protein is produced by the liver.
研究人員們正在探索此策略以開發一種，供因於心臟及神經中，錯誤折疊蛋白質累積，引發之罕見遺傳性疾病，遺傳性轉甲狀腺素蛋白澱粉樣變性使用的單劑量療法。這種疾病是以mRNA為基礎之CRISPR基因療法的理想標的。因為，該標的蛋白質是由肝臟所產生。
Because most drugs pass through the liver, this makes it easier to deliver CRISPR-Cas9 mRNA to its target. In the next few years, a new generation of more precise mRNA-based genome editing therapies will enter clinical trials.
因為，大多數藥物通過肝臟。因此，這使其更容易將CRISPR-Cas9的mRNA 遞送至其標的。於未來幾年，新一代更精確之以mRNA為基礎的基因體編輯療法，將進入臨床試驗。
圖2. 由於引發COVID-19(金色)的病毒及其他RNA病毒會透過胞內體進入細胞中，因此mRNA藥物雜質能引發類似的免疫反應。
Because the virus that causes COVID-19 (gold) and other RNA viruses enter cells through endosomes, mRNA drug impurities can elicit similar immune responses.
For treatments that need a specific protein to be present in the body for long periods of time or need to prompt little to no immune reaction, further advancements in mRNA technology are necessary to extend mRNA’s half-life and eliminate immune-triggering contaminants.
就需要特定蛋白質存在於人體內達長時間，或需要幾乎不引起免疫反應的療法而言，在mRNA技術上，需進一步的進展，來延長mRNA的半衰期，及消除觸發免疫力的污染物質。
Notable new developments in these areas include using computational algorithms to optimize mRNA sequences in ways that enhance their stability and engineering RNA polymerases that introduce fewer side products that may cause an immune response.
在此些領域中，值得注意的新發展包括，使用計算演算法，以增強其穩定性及工程改造，引進較少可能引起免疫反應之副產物的RNA聚合酶方法，來最佳化mRNA序列。
Further advancements have the potential to enable a new generation of safe, durable and effective mRNA therapeutics for applications beyond vaccines.
進一步的進展具有，能使新一代安全、持久且有效的mRNA療法，供疫苗以外之諸多用途使用的潛力。
網址：https://theconversation.com/drugs-of-the-future-will-be-easier-and-faster-to-make-thanks-to-mrna-after-researchers-work-out-a-few-remaining-kinks-215199
翻譯：許東榮
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