What shape are your cells? Squishy cylinders? Jagged zig-zags? You probably don’t think much about the bodies of these building blocks, but at the microscopic level, small changes can have huge consequences. And while some adaptations change these shapes for the better, others can spark a cascade of debilitating complications. This is the story of sickle-cell disease.
你的細胞是什麼形狀? 濕軟的圓柱狀?鋸齒狀的 Z 字形? 對這些組成積木的基本形體, 你可能不太會多想, 但從顯微層級來看,小小的改變 可能會造成大大的不同。 有些時候,適應作用 會將細胞形狀做更理想的改變, 但也有些時候,會造成 一連串讓人虛弱的併發症。 這是個關於鐮形血球貧血症的故事。
Sickle-cell disease affects the red blood cells, which transport oxygen from the lungs to all the tissues in the body. To perform this vital task, red blood cells are filled with hemoglobin proteins to carry oxygen molecules. These proteins float independently inside the red blood cell’s pliable, doughnut-like shape, keeping the cells flexible enough to accommodate even the tiniest of blood vessels. But in sickle cell disease, a single genetic mutation alters the structure of hemoglobin. After releasing oxygen to tissues, these mutated proteins lock together into rigid rows. Rods of hemoglobin cause the cell to deform into a long, pointed sickle. These red blood cells are harder and stickier, and no longer flow smoothly through blood vessels. Sickled cells snag and pile up– sometimes blocking the vessel completely. This keeps oxygen from reaching a variety of cells, causing the wide range of symptoms experienced by people with sickle-cell disease.
鐮形血球貧血症會影響紅血球, 紅血球會將氧氣從肺部 運送至全身各處的組織。 為了進行這項攸關生死的任務, 紅血球充滿了血紅蛋白, 用來攜帶氧分子。 這些蛋白質各自獨立,漂浮在 紅血球的圓滑甜甜圈形狀中, 讓細胞有足夠的彈性, 可以配合最小的血管。 但若得了鐮形血球貧血症, 一個基因突變 就會改變血紅素的結構。 將氧氣釋放到組織中之後, 這些突變的蛋白質 就會堅固地鎖成一列, 血紅素形成的長條,造成細胞變形, 成為長形尖頭的鐮刀狀。 這些紅血球比較硬也比較黏, 無法再像原本那樣順暢地流過血管。 鐮狀細胞會擱淺然後堆疊起來—— 有時會完全阻塞血管。 這麼一來,氧氣就無法 被遞送給許多細胞, 因而造成多種症狀
Starting when they’re less than a year old, patients suffer from repeated episodes of stabbing pain in oxygen-starved tissues. The location of the clogged vessel determines the specific symptoms experienced. A blockage in the spleen, part of the immune system, puts patients at risk for dangerous infections. A pileup in the lungs can produce fevers and difficulty breathing. A clog near the eye can cause vision problems and retinal detachment. And if the obstructed vessels supply the brain the patient could even suffer a stroke.
出現在鐮形血球貧血症患者身上。 從還不到一歲的時候, 病人因組織亟需氧氣 而一再飽受刺痛的折磨。 血管發生栓塞的位置, 會決定病人的症狀為何。 脾臟是免疫系統的一部分, 如果發生阻塞, 就會讓病人有受到致命感染的風險。 若堆積發生在肺部, 可能會造成發燒和呼吸困難。 眼睛附近的栓塞可能會導致 視力問題和視網膜剝離。 如果供血到大腦的血管被阻塞, 病人甚至有可能中風。
Worse still, sickled red blood cells also don’t survive very long— just 10 or 20 days, versus a healthy cell’s 4 months. This short lifespan means that patients live with a constantly depleted supply of red blood cells; a condition called sickle-cell anemia.
更糟糕的是,鐮狀紅血球的 存活時間不長—— 只有十或二十天,相對之下, 健康的紅血球可以存活四個月。 存活時間這麼短,就表示 病人經常會遇到紅血球供應不足; 這種病症叫做鐮狀細胞性貧血。
Perhaps what’s most surprising about this malignant mutation is that it originally evolved as a beneficial adaptation. Researchers have been able to trace the origins of the sickle cell mutation to regions historically ravaged by a tropical disease called malaria. Spread by a parasite found in local mosquitoes, malaria uses red blood cells as incubators to spread quickly and lethally through the bloodstream.
也許,這種惡性突變 最讓人驚訝的一點是, 它原本是種為了利於生存 而做的演化適應。 研究者在追蹤鐮狀細胞突變的 源頭上,已經可以追溯到 史上被瘧疾這種熱帶疾病 所蹂躪的地區。 瘧疾由寄生在當地 蚊子身上的瘧原蟲傳播, 瘧原蟲會把紅血球當作孵卵器來使用, 能透過血液來傳播,快速又致命。
However, the same structural changes that turn red blood cells into roadblocks also make them more resistant to malaria. And if a child inherits a copy of the mutation from only one parent, there will be just enough abnormal hemoglobin to make life difficult for the malaria parasite, while most of their red blood cells retain their normal shape and function. In regions rife with this parasite, sickle cell mutation offered a serious evolutionary advantage. But as the adaptation flourished, it became clear that inheriting the mutation from both parents resulted in sickle-cell anemia.
然而,將紅血球轉變成 路障的這種結構改變, 也讓它們更能抵抗瘧疾。 如果孩子只從雙親之一 遺傳到這種突變, 孩子就會有足夠的異常血紅素 讓瘧原蟲難以生存, 同時大部分的紅血球 還保持正常的形狀和功能。 在瘧原蟲充斥的地區, 鐮狀細胞突變反而是 演化上的一大優勢。 但,隨著這種適應作用越來越常見, 開始發現,從雙親遺傳到突變 會導致鐮狀細胞性貧血。
Today, most people with sickle-cell disease can trace their ancestry to a country where malaria is endemic. And this mutation still plays a key role in Africa, where more than 90% of malaria infections occur worldwide. Fortunately, as this “adaptation” thrives, our treatment for sickle cell continues to improve. For years, hydroxyurea was the only medication available to reduce the amount of sickling, blunting symptoms and increasing life expectancy. Bone marrow transplantations offer a curative measure, but these procedures are complicated and often inaccessible. But promising new medications are intervening in novel ways, like keeping oxygen bonded to hemoglobin to prevent sickling, or reducing the stickiness of sickled cells. And the ability to edit DNA has raised the possibility of enabling stem cells to produce normal hemoglobin. As these tools become available in the areas most affected by malaria and sickle cell disease, we can improve the quality of life for more patients with this adverse adaptation.
現今,大部分的鐮形血球貧血症患者 都有祖先來自曾經有瘧疾流行的國家。 這種突變仍在非洲扮演關鍵角色, 全世界有九成以上的瘧疾 發生在非洲。 幸運的是,隨著這種 「適應作用」越來越盛, 我們針對鐮狀細胞的治療 也持續不斷改善。 過去多年來,只有羥基尿素 這種藥物可以用來 減少鐮狀化的量、 減輕症狀,來延長壽命。 骨髓移植是一種治療的方式, 但這類手術很複雜, 且通常難以取得。 但有些前景看好的新藥物, 能夠以創新的方式干預治療, 比如讓氧氣和血紅素維持結合, 來預防鐮狀化, 或是減低鐮狀細胞的黏度。 而編輯 DNA 的能力 也提升了讓幹細胞產生 正常血紅素的可能性。 當受瘧疾和鐮狀細胞病 影響最大的區域 有了這些選項後, 我們就能協助這種 不良適應作用的病人 改善生活品質。