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Arthritis and botulinum toxin
關節炎與肉毒桿菌毒素
Something to celebrate
值得慶賀
Botulinum toxin may help relieve chronic pain
肉毒桿菌毒素也許能夠幫助緩解慢性疾病的痛苦
ARTHRITIS is the bane of millions of lives. Though it comes in many forms, their common theme is inflammation of the tissues around a joint in the skeleton. Treatment is merely palliative: anti-inflammatory drugs, painkillers or both. But a piece of research published this week in Biochemistry, by Edwin Chapman of the University of Wisconsin and his colleagues, offers arthritis sufferers hope from a strange quarter: botulinum toxin.
關節炎是數百萬人的噩夢。關節炎有多種形式，但它們共同的特征是關節處組織的炎癥反應。對此的治療手段往往是治標不治本：消炎藥，止痛藥，或者兩者同時用。但是由威斯康辛大學埃德文?查普曼博士以及他的同事們在本周生物化學雜志上的發表的一項研究，為關節炎患者提供了希望：肉毒桿菌毒素。
This toxin is one of the most dangerous substances on earth. It is made by a bacterium called Clostridium botulinum. Even a small amount (less than a microgram) is enough to kill a healthy adult. The toxin molecules attach themselves to a protein called synaptotagmin, which is found on the surface membranes of nerve cells at their junctions with muscle cells. Thence they are ingested into the cell, where they disable another protein, SNAP-25, the role of which is to help release a chemical messenger called acetylcholine. This messenger's job is to tell muscle cells to contract. Without that signal, muscles stops working. If this happens all over the body, death is rapid.
這種毒素是地球上最危險的物質之一，它是由一種叫肉毒桿菌的細菌合成。僅僅很小的量（小于一微克）就足以殺死一個健康成年人。這種毒素能結合到一種叫做synaptotagmin（SYT）的蛋白上，SYT則位于神經肌肉接頭處神經細胞的細胞膜表面。然后這種毒素被吞入細胞內部，進而讓另外一個叫SNAP-25的蛋白失活，SNAP-25的作用是幫助一種叫乙酰膽堿的化學信使的釋放。這種化學信使的作用則是讓肌肉細胞進行收縮。沒有這種信號的話，肌肉便停止工作了。如果全身都發生這樣的情況，死亡便接踵而來。
Inject the toxin locally, though, and you can do some good. It wipes away frown lines and other wrinkles, which are caused by overstimulated muscles, thus allowing ageing celebs to appear on the covers of gossip magazines without embarrassment. More seriously, it is used to treat disorders ranging from headaches to muscle spasms. It only works, however, in cells that have synaptotagmin on their surfaces. Which is where Dr Chapman comes in.
然而局部注射肉毒素還能帶來好處。它能撫平額頭和其他部位的皺紋，這些皺紋恰恰是因為肌肉被過度刺激引起的。它使得那些上了年紀的名流們毫無尷尬的出現在街頭雜志的封面。它更為嚴肅的用途是治療各種生理紊亂，包括從頭痛到肌肉痙攣。然而，它僅僅能在那些表面具有SYT蛋白的細胞中起作用，這正是查普曼博士的切入點。
Inflammation is also caused by chemical signalling. Cells called macrophages summon all sorts of others to an injury, to try to repair it. If repair cannot be effected, though (as is the case in arthritis), the signalling never stops. The swelling causes pain, and the patient suffers. But macrophage signalling also involves SNAP-25, so Dr Chapman thinks he can use botulinum toxin to shut the cells up.
炎癥反應同樣是由化學信號引起的。巨噬細胞召集其他免疫細胞到達受傷處，并試圖修復傷害。但如果修復不起作用（如同關節炎的情況），則這些信號就不會停止。腫痛造成痛苦，而病人只能忍受。但是巨噬細胞的信號通路中也包括SNAP-25，因此查普曼博士想，他能夠用肉毒素來關閉這些免疫細胞。
The problem is that macrophages have no synaptotagmin on their surfaces. They do, though, have other proteins, called Fc receptors. What is needed is a way to get toxin molecules to attach themselves to Fc receptors. And this is what Dr Chapman thinks he has managed. His trick is to link each molecule to an antibody. An antibody is a protein that binds to a hostile invading organism. If this does not kill the invader outright, then it acts as a flag for the bug in question to be eaten by a macrophage. That happens when the antibody that is attached to the invader also attaches itself to an Fc-receptor molecule. This done, the invader is ingested.
問題在于，巨噬細胞的表面并沒有SYT蛋白，他們表面有的是另外一種被稱為Fc受體的蛋白。現在只需要找到一個辦法，讓肉毒素結合到Fc受體上去，而查普曼博士認為，他辦到了這一點。他的絕招是將每個分子與抗體連接起來。抗體是一種能結合入侵有機體的分子，如果抗體不能馬上殺死入侵者，則它將作為入侵者的一個標記，使得它們有可能被巨噬細胞所吞噬，這個過程只有當結合在入侵者上的抗體同時也能和Fc受體分子結合時才會發生，而這個步驟一完成，則入侵者就被吞噬了。
Dr Chapman's plan was to use this mechanism to get macrophages to eat toxin molecules. Once inside, they would disable SNAP-25 and thus stop the release of signalling molecules in the way they do in nerve cells. The result, the theory goes, would be an end to the chronic inflammation that arthritis causes, and thus to the chronic pain.
查普曼博士的計劃是，利用這個機制，讓巨噬細胞把肉毒素吞進去，而進入細胞之后，它就能使SNAP-25失去活性，從而像在神經細胞中一樣，阻止信號分子的釋放。如果這個理論可行，那么由關節炎所導致的慢性炎癥將被終結，同時被終結的，還有長期以來的痛苦。
The first stage works. The toxin/antibody complex successfully gloms onto the macrophages. The toxin does get inside them. And the cells do stop signalling. It is a long way from there to a treatment, but Dr Chapman has made the trick work in mice as well as Petri dishes (injecting the complex does, indeed, stop macrophages recruiting). Many more animal trials will be needed before it can be tested on people. But for those who suffer the chronic pain of arthritis, it is a hopeful start.
第一步看起來是可行的。肉毒素與抗體的復合物成功地黏附上巨噬細胞，肉毒素確實進入了巨噬細胞內部，這些細胞也的確中止了信號通路。從這一步到治療仍有很長的路要走，但是查普曼博士已經用這個方法在培養皿的細胞中和在老鼠身上獲得了成功（注入這種復合物確實阻止了巨噬細胞的招募）。在人體上進行測試前，還需要完成更多的動物實驗，但是對于那些正在長期忍受關節炎痛苦的人們來說，這是一個充滿希望的開始。
