From the smallest single-celled organism to the largest creatures on earth, every living thing is defined by its genes. The DNA contained in our genes acts like an instruction manual for our cells. Four building blocks called bases are strung together in precise sequences, which tell the cell how to behave and form the basis for our every trait. But with recent advancements in gene editing tools, scientists can change an organism’s fundamental features in record time. They can engineer drought-resistant crops and create apples that don’t brown. They might even prevent the spread of infectious outbreaks and develop cures for genetic diseases. CRISPR is the fastest, easiest, and cheapest of the gene editing tools responsible for this new wave of science. But where did this medical marvel come from? How does it work? And what can it do?
從最小的單細胞有機體, 到地球上最大的動物, 所有生物都是 由它的基因所定義的。 我們基因中的 DNA 就像是 給我們細胞看的說明書。 四種叫做「鹼基」的積木, 會依照特定的順序串在一起, 告訴細胞該做出什麼行為, 並形成我們每一項特點的基礎。 但靠著近期在基因工具的進展, 科學家能夠在最短時間內 改變有機體的基本特徵。 他們能設計出抗旱的作物, 創造出不會變成褐色的蘋果。 他們甚至可能可以預防 感染性疾病爆發的擴散, 並開發出基因疾病的解藥。 CRISPR 是最快速、最簡單, 且最便宜的基因編輯工具, 會有這一波科學新潮流, 就是因為它。 但這項醫學奇蹟是從哪裡來的? 它如何運作?它能做什麼? 很讓人訝異的是,CRISPR 其實是一種自然過程,
Surprisingly, CRISPR is actually a natural process that’s long functioned as a bacterial immune system. Originally found defending single-celled bacteria and archaea against invading viruses, naturally occurring CRISPR uses two main components. The first are short snippets of repetitive DNA sequences called “clustered regularly interspaced short palindromic repeats,” or simply, CRISPRs. The second are Cas, or “CRISPR-associated” proteins which chop up DNA like molecular scissors. When a virus invades a bacterium, Cas proteins cut out a segment of the viral DNA to stitch into the bacterium’s CRISPR region, capturing a chemical snapshot of the infection. Those viral codes are then copied into short pieces of RNA. This molecule plays many roles in our cells, but in the case of CRISPR, RNA binds to a special protein called Cas9. The resulting complexes act like scouts, latching onto free-floating genetic material and searching for a match to the virus. If the virus invades again, the scout complex recognizes it immediately, and Cas9 swiftly destroys the viral DNA.
長久以來就以細菌 免疫系統的形式在運作。 最早發現它會保護 單細胞細菌和古菌, 抵抗來襲的病毒, 自然發生的 CRISPR 會使用兩種主要元件。 第一種是重覆 DNA 序列的片斷, 叫做「群聚且有規律間隔的 短回文重覆序列」, 或簡稱為 CRISPRs。 第二種是 Cas, 即 CRISPR 關聯蛋白, 它像是分子剪刀一樣 可以切碎 DNA。 當病毒攻擊細菌時, Cas 蛋白會把病毒 DNA 的一部分切下來, 將它縫到細菌的 CRISPR 區域, 取得感染的化學快照。 接著,那些病毒碼 會被複製成短的 RNA。 RNA 這種分子在我們的 細胞中扮演許多角色, 但就 CRISPR 的情況來說, RNA 會和特別的蛋白質 Cas9 結合 。 產生出來的複合物, 功能就像是偵察兵, 佔據自由浮動的基因材料, 搜尋和病毒一模一樣的目標。 如果病毒再次侵襲, 偵察兵複合物就會馬上認出它, Cas9 會快速地摧毀病毒 DNA。
Lots of bacteria have this type of defense mechanism. But in 2012, scientists figured out how to hijack CRISPR to target not just viral DNA, but any DNA in almost any organism. With the right tools, this viral immune system becomes a precise gene-editing tool, which can alter DNA and change specific genes almost as easily as fixing a typo.
很多細菌都有這種防禦機制。 但,2012 年,科學家 找出了方法來劫持 CRISPR, 讓它的目標不只是病毒 DNA, 而是幾乎任何 有機體中的任何 DNA。 用對了工具,這種病毒免疫系統 就變成了精確的基因編輯工具, 能用來修改 DNA, 改變特定的基因, 幾乎就像打錯字的修改一樣容易。
Here’s how it works in the lab: scientists design a “guide” RNA to match the gene they want to edit, and attach it to Cas9. Like the viral RNA in the CRISPR immune system, the guide RNA directs Cas9 to the target gene, and the protein’s molecular scissors snip the DNA. This is the key to CRISPR’s power: just by injecting Cas9 bound to a short piece of custom guide RNA scientists can edit practically any gene in the genome.
在實驗室中,它是這樣運作的: 科學家設計出一個「嚮導」RNA, 符合他們想要編輯的基因, 將它附著到 Cas9 上。 就像 CRISPR 免疫系統中的病毒 RNA, 嚮導 RNA 會指示 Cas9 去找目標基因, 該蛋白質的分子剪刀會切斷 DNA。 這就是 CRISPR 如此強大的關鍵: 只要把 Cas9 注射到短短一小段 訂製的嚮導 RNA 中, 科學家就可以編輯 基因組中的幾乎任何基因。
Once the DNA is cut, the cell will try to repair it. Typically, proteins called nucleases trim the broken ends and join them back together. But this type of repair process, called nonhomologous end joining, is prone to mistakes and can lead to extra or missing bases. The resulting gene is often unusable and turned off. However, if scientists add a separate sequence of template DNA to their CRISPR cocktail, cellular proteins can perform a different DNA repair process, called homology directed repair. This template DNA is used as a blueprint to guide the rebuilding process, repairing a defective gene or even inserting a completely new one.
一旦 DNA 被切斷, 細胞會嘗試修復它。 通常,叫做核酸酶的蛋白質 會把破裂的邊緣修整好, 將它們重新接合起來。 但這種修復過程, 也就是「非同源染色體末端連接」, 很容易犯錯,且可能會導致 鹼基多出來或不足。 結果產生出來的基因通常不能用, 會被關掉(去活化)。 然而,如果科學家將一個 個別的模板 DNA 序列 加到他們的 CRISPR 雞尾酒裡, 細胞蛋白質就能執行 一種不同的 DNA 修復過程, 稱為同源介導修復。 這種模板 DNA 被用來當作藍圖, 引導重建的過程。 修復缺陷基因, 或甚至插入全新的基因。 有修復 DNA 錯誤的能力,
The ability to fix DNA errors means that CRISPR could potentially create new treatments for diseases linked to specific genetic errors, like cystic fibrosis or sickle cell anemia. And since it’s not limited to humans, the applications are almost endless. CRISPR could create plants that yield larger fruit, mosquitoes that can’t transmit malaria, or even reprogram drug-resistant cancer cells. It’s also a powerful tool for studying the genome, allowing scientists to watch what happens when genes are turned off or changed within an organism.
就表示可能可以用 CRISPR 來創造新的療法, 治療與特定基因錯誤有關的疾病, 比如囊腫性纖維化 或鐮狀細胞性貧血症。 既然它不只限於人類, 應用範圍幾乎是無限大的。 CRISPR 可以創造出 果實更大的植物, 不會傳播瘧疾的蚊子, 或甚至將有抗藥性的 癌細胞重新編程。 在研究基因組方面, 它也是強大的工具, 讓科學家可以看到, 當基因被關掉時, 或在有機體內改變時, 會發生什麼事。
CRISPR isn’t perfect yet. It doesn’t always make just the intended changes, and since it’s difficult to predict the long-term implications of a CRISPR edit, this technology raises big ethical questions. It’s up to us to decide the best course forward as CRISPR leaves single-celled organisms behind and heads into labs, farms, hospitals, and organisms around the world.
CRISPR 還不完美。 它不見得能只做出 我們想要做的改變, 且因為很難預測長期來看 CRISPR 編輯會有什麼意涵, 這項技術免不了會有 很大的倫理問題。 我們要決定未來 怎麼走才是最好的, 因為 CRISPR 不再 只用於單細胞有機體, 它已經要邁入全世界的 實驗室、農田、 醫院,以及生物。