播放GIF
看完影片以後，是不是感慨良多？心疼影片中的患者，感動於「勇哥」的所為，痛恨醫藥公司的天價葯？小編個人覺得吧，對患者的同情並不一定意味著要把醫藥公司妖魔化。現在一個新葯的上市，從發現，到篩選，到臨床前的藥理、葯代、毒理研究，再到I，II，III期臨床實驗（小編不是學葯的，中間還漏掉了不少的步驟），整個流程下來，少則十年，上不封頂。
以影片中提到的「格列寧」的原型——「格列衛」為例，該葯的研發歷經半個多世紀，投入的研究經費上百億美元，我們才能看到今天這個葯的樣子。而仿製葯不需要經歷醫藥公司前四十餘年的失敗和臥薪嘗膽，成本自然低。我們如果隻以原材料的成本來判斷葯的價值，那就好像用紙張的材料來衡量一本書的價值，用顏料的用量來衡量一幅畫的價值，用石頭的重量來衡量一座雕塑的價值。如果每一次數十載的研發都被輕而易舉的仿製，那最後原創被擠垮後，還能向誰去仿製呢？
當然啦，拍電影嘛，如果不找一個面目可憎的形象來承擔我們的憤怒，每一方都很可憐，我們憋屈的憤懣該如何釋放呢？所以影片以一個可惡的奸商形象代表醫藥公司，並適當誇大了實際生活中格列衛正版葯和仿製葯的差價，也是為了增加戲劇的衝突性所作的處理啦。
所以，我們要明確一下，現實生活中，我們的主要敵人並不是醫藥公司，而是我們共同面對的疾病——慢性白血病。為了更好地理解這部影片，我們有必要好好認識一下慢性白血病這個疾病。它的治療現狀是怎麼樣的？除了吃格列衛以外，還有什麼樣的治療手段？得了白血病就等於判了死刑了嗎？
首先慢性白血病包括慢性粒細胞性白血病和慢性淋巴細胞性白血病，《葯神》中提到的「慢粒」就是前者。以慢粒為例，它的首選治療確實就是格列衛——影片中化名成了格列寧——主要成份是甲磺酸伊馬替尼片，是一種酪氨酸激酶抑製劑，可抑製白細胞增殖。超過80%的患者可通過服藥達到長期生存狀態。但通常不推薦停葯，長期服藥可能造成格列衛耐葯，而轉入二線或三線治療。所以，可以說格列衛等藥物的存在，使慢性粒細胞性白血病不再是不治之症。而且即使服藥效果不佳的患者，還有化療、乾細胞移植和骨髓移植等選擇。
我們還是通過生動的影片講解來詳細了解一下慢性白血病吧！
（影片較大，建議在wifi下觀看）
With chronic leukemia, 「leuk」 refers to white blood cells, and 「emia」 refers to the blood; so in chronic leukemia there are lots of partially developed white blood cells in the blood over a long period of time. These partially developed white blood cells interfere with the development and function of healthy white blood cells, platelets, and red blood cells.
慢性白血病的英文名稱「leukemia」中，「leuk」意為白細胞，「emia」意為血液，慢性白血病指的是血液中長期大量存在僅部分分化的白細胞。這些部分分化的白細胞會對健康白細胞、血小板、紅細胞的分化和功能造成影響
Now, every blood cell starts its life in the bone marrow as a hematopoietic stem cell. Hematopoietic stem cells are pluripotent -- meaning that they can give rise to both myeloid or lymphoid blood cells.
每個血細胞最初都由骨髓中一個造血乾細胞分化而來，造血乾細胞擁有多重分化潛能，意思是它既可以分化成髓樣血細胞，也可分化成淋巴樣血細胞。
If a hematopoietic stem cell develops into a myeloid cell, it』ll mature into an erythrocyte -- or a red blood cell, a thrombocyte -- or a platelet, or a leukocyte -- or a white blood cell, like a monocyte or granulocyte. Granulocytes are cells with tiny granules inside of them -- they include neutrophils, basophils, and eosinophils.
如果造血乾細胞分化成髓樣細胞，它最終可能分化成成熟的紅細胞、血小板或白細胞，後者包括單核細胞和粒細胞。粒細胞內通常含有微小的顆粒，粒細胞包括中性、鹼性和酸性粒細胞。
If a hematopoietic stem cell develops into a lymphoid cell, on the other hand, it』ll mature into some other kind of leukocyte: a T cell, a B cell, or a natural killer cell, which are referred to as lymphocytes.
如果造血乾細胞分化成淋巴樣細胞，它最終可能分化為其他類型的白細胞，如T細胞、B細胞或自然殺傷細胞（NK細胞），它們都稱為淋巴細胞。
Once the various blood cells form, they leave the bone marrow, and travel around the blood, or settle down in tissues and organs like the lymph nodes and spleen.
當各種類型的血細胞分化完成後，它們就會離開骨髓，或隨血液在體內流動，或「定居」於淋巴結和脾臟等組織或器官內。
Chromosomal abnormality in hematopoietic stem cells that are destined to become leukocytes is the most common cause of chronic leukemia. Some examples of abnormalities include a chromosomal deletion, where part of a chromosome is missing, a trisomy, where there』s one extra chromosome, and a translocation, where two chromosomes break and swap parts with one another.
最終分化成白細胞的造血乾細胞內的染色體異常，是慢性白血病的最常見病因。常見的染色體異常的情況包括染色體缺失，即部分染色體物質丟失；或三倍體，即多出一條額外的染色體；或染色體易位，即兩條染色體的部分物質發生斷裂和交換。
Now there are two types of chronic leukemia. The first is chronic myeloid leukemia, CML, which is caused by a particular chromosomal translocation that affects granulocytes. The second is chronic lymphocytic leukemia, CLL, which is caused by a variety of chromosomal mutations that affect lymphocytes, in particular B cells.
慢性白血病分為兩大類，第一類稱為慢性髓細胞樣白血病（慢粒），它是由於影響粒細胞分化的特定的染色體易位引起的；第二種類型稱為慢性淋巴細胞性白血病（慢淋），它是由多種染色體變異引起的，主要累及淋巴細胞，尤其是B細胞。
Both CML and CLL cause cells to mature only partially, and that』s a key distinction from acute leukemias where the cells don』t mature at all. As a result, these abnormal, premature leukocytes don』t work effectively, which weakens the immune system.
慢淋和慢粒都會造成細胞部分分化，這也是它們與急性白血病的鑒別要點。急性白血病時血細胞完全不能分化為成熟細胞，其結果是，這些異常、不成熟的白細胞無法正常執行功能，從而使免疫功能下降。
In addition, the chromosomal changes alters the cell』s normal cell cycle. As a result, in CML the cells start to divide way too quickly and in CLL the cell』s don』t die when they should -- and in both situations, we』re left with way too many of these premature cells.
另外，染色體的改變還會影響正常的細胞代謝周期，結果，在慢粒時細胞分化過快，而在慢淋時細胞不能正常凋亡。兩種情況下，體內都會出現過多未成熟血細胞。
So over time, premature leukocytes accumulate in the bone marrow, until eventually they spill out into the blood. Now some of these guys settle down in organs and tissues across the body, but others keep circulating in the blood. With a bunch of extra cells in the blood, all the healthy cells get 「crowded out」, and it』s tough for them to survive with the extra competition for nutrients. This causes cytopenias, or a reduction in the number of healthy blood cells, like anemia, which is a reduction of healthy red blood cells, thrombocytopenia, a reduction of healthy platelets, and leukopenia, or a reduction of healthy leukocytes.
隨著時間推移，未成熟的白細胞在骨髓內累積，最終會湧向血液循環。有的血細胞停留於器官和組織中，而其他血細胞則在血液中不停流動。血液中多出的這些異常血細胞，會逐漸排擠正常的血細胞，正常血細胞將很難在額外的營養爭奪中生存，於是便會造成血細胞減少，即健康血細胞的數量下降。例如貧血，即健康紅細胞減少；或血小板減低，即健康血小板數目下降；或是白細胞減低，即健康白細胞數目下降。
In chronic myeloid leukemia, the most common cause is a chromosome translocation, which results in a Philadelphia chromosome. And that』s where a portion of chromosome 9』s long arm switches with a portion of chromosome 22』s long arm -- and we write that as t(9;22) -- t because it』s a translocation, and 9 and 22 because those are the chromosomes that switch genetic information. This results in a modified chromosome 9 and modified chromosome 22, and it』s the chromosome 22 that』s called the Philadelphia chromosome.
慢性髓樣細胞白血病最常見的病因是染色體易位，形成「費城染色體」，即9號染色體長臂部分區段，與22號染色體長臂發生易位。記為t(9;22) —t代表易位，9和22代表發生基因資訊交換的兩條染色體。結果是造成了9號和22號染色體都發生了改變，其中發生改變的22號染色體被稱為費城染色體。
So, in the Philadelphia chromosome, a chromosome 22 gene, which is the BCR gene, ends up sitting right next to a chromosome 9 gene, the ABL gene. When they』re combined it forms a fusion gene called BCR ABL, which codes for a protein also called BCR ABL, and that protein activates enzymes called tyrosine kinases. Some of these tyrosine kinases are like on/off switches for various cellular functions, including cell division. So when the BCR ABL fusion protein turns on these tyrosine kinases, it forces myeloid cells to keep dividing quicker than they should, which causes a buildup of the premature leukocytes in the bone marrow, that eventually spill into the blood.
若出現了費城染色體，那麼22號染色上的BCR基因，會與9號基因上的ABL基因相連，兩者結合後會融合成稱為BCR-ABL的基因，編碼一種稱為BCR-ABL的蛋白。這種蛋白將會激活酪氨酸激酶，某些酪氨酸激酶就像開關一樣，對一些細胞功能進行調控，包括細胞的分化。當BCR-ABL融合蛋白激活酪氨酸激酶後，它就會迫使髓樣細胞不停地超速分化，最終會導致骨髓中未成熟白細胞增多，並最終湧入血液循環。
（慢粒的主要病因——費城染色體的出現）
The premature leukocytes then move to the liver and spleen, causing swelling of those organs or 「hepatosplenomegaly」. And because these CML cells divide quicker than they should, there』s a high chance that further genetic mutations can happen! And if that happens, CML might progress and accelerate into a more serious acute leukemia, which is called a blast crisis, because the totally immature cells of acute leukemias are referred to as blasts. A lot of cases of these blast crises include the formation of a trisomy on chromosome number 8, or the doubling of the Philadelphia chromosome.
這些未成熟白細胞會進入肝臟和脾臟，造成這些器官的腫脹，稱為「肝脾腫大」。由於這些慢粒細胞分化過快，它們發生進一步基因突變的機率也大大增加，這種情況下慢粒就可能進展、加速，成為更加嚴重的急性白血病，稱為慢粒白血病急變期。急性期白血病中完全不能分化的細胞，也稱為急變細胞。許多慢粒急變的病例都涉及到8號染色體三倍體的形成，或是費城染色體的倍增。
（慢粒引起肝脾腫大）
（慢粒進入急變期）
In chronic lymphocytic leukemia, the most likely cause is also mutation in the cells』 chromosomes -- we just don』t know which particular mutation, or mutations. Whatever the case the result is that B cells start to interfere with the pathways of B cell receptors, which should only be signalled during infection to activate a few specific tyrosine kinases. Interference with Bruton』s tyrosine kinase, for example, is probably what stops CLL cells from maturing fully, and it』s similar interference with other tyrosine kinases that allows them to die slower than they divide, which is why they build up.
在慢性淋巴細胞性白血病中，主要的病因同樣是細胞染色體突變，隻不過我們還不清楚具體發生了哪些突變。不論原因如何，其結果是B細胞開始對B細胞受體通路產生影響，而B細胞受體通路原本隻應在感染時激活，以活化一些特定的酪氨酸激酶。例如，對Bruton』s酪氨酸激酶產生的影響，可能是造成慢淋細胞無法完全成熟的主要原因；對其他酪氨酸激酶產生的類似影響，都會造成細胞分化速度超過凋亡速度，白細胞因而發生累積。
These premature cells always express particular proteins on their surfaces, including CD5, CD19, and CD23. The CD part stands for 「cluster of differentiation」, because these are common surface proteins, which can be used to differentiate between the lymphocytes. And despite CLL cells being B lymphocytes, they express the CD5 protein, which is a lot more common in T lymphocytes.
這些未成熟細胞總是會在細胞表面表達特定的蛋白，包括CD5，CD19以及CD23。CD是「分化抗原簇」的英文縮寫，這些表面蛋白經常用來區分各類的淋巴細胞。儘管慢淋細胞是B型淋巴細胞，它們卻表達在T淋巴細胞上更為常見的CD5蛋白。
Anyway, these premature leukocytes build up in the bone marrow and eventually spill into the blood, like in CML. Some of these cells then move to the lymphatic system, where normal lymphocytes go, and although this does include the spleen, the lymph nodes are prioritized. This causes swelling of the lymph nodes, or 「lymphadenopathy」.
總之，這些未成熟白細胞在骨髓中累積，最終湧入血液中，與慢粒情況相似。與正常淋巴細胞一樣，這些未成熟細胞也會進入淋巴系統，脾臟也有可能受累，但最先受累及的通常是淋巴結，從而造成淋巴結腫大，也稱「淋巴結病」。
Then eventually, B cells in these nodes will accumulate into distinct masses, or 「lymphomas」, which is why mature CLL is sometimes called small lymphocytic lymphoma.
最終，淋巴結中B細胞的累積將會，形成特徵性腫塊，稱為「淋巴瘤」。所以慢性淋巴細胞白血病有時也稱為小淋巴細胞性淋巴瘤。
Further progression might take the form of a Richter transformation, where those small, pretty harmless lymphomas collect into sizable masses that damage the body. And, because B cells normally work in the immune system, the reduced or adverse functioning of CLL cells might result in autoimmune hemolytic anemia, where the cells attack the body』s own red blood cells and kill them off, or hypogammaglobulinemia, where the cells don』t produce enough gamma globulins.
疾病繼續進展則可發展為Richter綜合征。此時這些體積小而基本無害的淋巴瘤，體積不斷增大以致對身體造成損害。此外，因為B細胞通常在免疫系統中起作用，慢淋細胞的功能較正常降低甚至作用相反，由此可能造成自身免疫性溶血性貧血，即這些免疫細胞開始攻擊、殺死自身的紅細胞；也可造成低丙種球蛋白血症，即免疫細胞無法制造足夠的丙種球蛋白。
Symptoms of both CML and CLL include fatigue, because of anemia, easier bleeding, because of thrombocytopenia, and more frequent infection, because of leukopenia. In CML the hepatosplenomegaly of CML often causes a feeling of abdominal fullness, while the lymphadenopathy of CLL often causes mild, but localized pain in the lymph nodes.
慢粒和慢淋的癥狀都包括，貧血引起的乏力、血小板減少造成的出血傾向和白細胞減少造成的感染傾向。在慢粒中，肝脾腫大還常常引起腹脹感；而慢淋引起的淋巴結病常常引起，輕微、局限性的淋巴結痛。
慢性白血病的癥狀其實就是各種正常血細胞減少引起的癥狀。《葯神》影片中人人帶口罩是由於患者正常白細胞減少，免疫力下降，易受各種感染。對於我們來說扛幾天就能扛過去的感冒，對於他們來說就可能會發展成肺炎；我們蹭破皮哪怕不管，兩三天也自愈了，但對於他們來說卻可能引起嚴重感染。所以單親媽媽所說的「有菌環境不方便」就是這麼個道理。
另外，各種電影裡最喜歡用來表現白血病的場面就是——流鼻血，這反映的是血小板下降引起的凝血功能障礙。不僅僅是流鼻血，即使是抽血化驗，一般人按上兩三分鐘就可止血，白血病患者哪怕按上半小時有時也會出現大片皮下瘀血；不敢參加體育活動，因為健康人眼中很正常的碰撞也會造成大片青紫。
The diagnosis of CML and CLL usually starts with a blood smear, which shows a lot of premature leukocytes. In CML, there are an increased number of granulocytes and monocytes and in CLL, there are often 「smudge」 cells on the blood smear -- immature B cells that have broken during the smear. For a conclusive diagnosis, genetic testing can be done to look for the Philadelphia chromosome in CML and to look for chromosomal defects in CLL.
慢粒和慢淋的診斷通常始於血塗片，血塗片上可見大量的未成熟白細胞。在慢粒中，粒細胞和單核細胞數量增加，而在慢淋中，可以看到「塗抹細胞」，這是未成熟B細胞在塗片過程中破裂而形成的。要獲得明確診斷，可以進行基因檢測，在慢粒中可以找到費城染色體，而在慢淋中可以發現染色體缺陷。
Treatment for CML always includes biological therapy, with a tyrosine kinase inhibitor aimed at stopping cell division caused by the BCR ABL protein. This is less effective for CLL though, as there』s no specific target. Other options for both CML and CLL include chemotherapy, stem cell transplants, or bone marrow transplants.
慢粒的治療通常都要用到生物治療。運用酪氨酸激酶抑製劑，以阻止BCR ABL蛋白造成的細胞分化過快。由於慢淋沒有特殊的藥物靶點，所以酪氨酸激酶抑製劑對其效果甚微。慢粒和慢淋的其他治療選擇還包括化療、乾細胞移植和骨髓移植。
《葯神》中提到的抗癌神葯格列寧，學名甲磺酸伊馬替尼片，其實就是一種酪氨酸激酶抑製劑。
好了，最後來點乾貨，小結一下有關慢性白血病的核心辭彙吧。
leukemia 白血病
hematopoietic stem cell 造血乾細胞
pluripotent 多能
myeloid blood cell 髓樣細胞
lymphoid blood cell 淋巴樣細胞
chromosomal deletion 染色體缺失
trisomy 三倍體
translocation 染色體易位
chronic myeloid leukemia 慢性髓細胞白血病（慢粒CML）
chronic lymphocytic leukemia 慢性淋巴細胞性白血病（慢淋CLL）
cytopenias 血細胞減少
anemia 貧血
thrombocytopenia 血小板減低
leukopenia 白細胞減低
Philadelphia chromosome 費城染色體
tyrosine kinases 酪氨酸激酶
hepatosplenomegaly 肝脾腫大
blast crisis 白血病急變期
cluster of differentiation 分化抗原簇
lymphadenopathy 淋巴結病
lymphomas 淋巴瘤
small lymphocytic lymphoma 小淋巴細胞性淋巴瘤
autoimmune hemolytic anemia 自身免疫性溶血性貧血
hypogammaglobulinemia 低丙種球蛋白血症
「smudge」 cells 塗抹細胞
tyrosine kinase inhibitor 酪氨酸激酶抑製劑
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