|
|
|
Intracellular junk and how to get rid of it细胞内垃圾及其清除 Cells have a lot of reasons to break down big molecules and structures into their component parts, and a lot of ways to do so. Unfortunately, one of the main reasons to break things down is because they have been chemically modified so that they no longer work, and sometimes these chemical modifications create structures that are so weird that none of the cell's degradation machinery works on them. 细胞有很多理由把大分子和结构降解，成为细胞的组成部分，也有很多办法用于降解。不幸地，把东西降解的主要理由之一，是这些东西已被化学修饰得不能再用，有时，这些化学修饰物创造了那么怪异的结构，以至于没有一部细胞降解机器能够对付它们。 This is very rare, but in the long run it adds up. The place where it adds up is called the lysosome, a special vessel that contains the most powerful degradation machinery in the cell; if something can't even be broken down there, it just stays there forever. This doesn't matter in cells that divide regularly, because division dilutes the junk away, but non-dividing cells gradually fill up with this stuff -- different types of stuff in different types of cell. 这种情况很罕见，但时间长了就会堆积。堆积的地方称为溶酶体，它是一种细胞中含有最强大降解机器的特殊容器；如果某些东西甚至不能被溶酶体所降解，它就会永远堆积在那儿。这在定期分裂的细胞中没问题，因为分裂会稀释这些垃圾，但是，不能分裂的细胞会逐渐充塞这样的垃圾Ñ不同类型的细胞堆积不同类型的垃圾。 The heart, the back of the eye, some nerve cells (especially motor neurons) and, most of all, white blood cells trapped within the artery wall all suffer from this. Eventually these cells can't take any more and they stop working right. This is the sole cause of atherosclerosis (the formation of lumps, called plaques, in the artery wall, which eventually burst and cause heart attacks and strokes). It is also important in several types of neurodegeneration and in macular degeneration (the main cause of blindness in the old). So it's very important to fix it. 心脏、眼的背面、某些神经细胞（特别是运动神经原），尤其是陷进动脉壁内的白血细胞，都会遭遇这种情况。这些细胞最终什么也干不成，只有停止工作。这是动脉硬化症的唯一原因（在动脉壁中形成斑块，最终爆发，引起心脏病发作和中风）。它对几个类型的神经性退化和黄斑变性（老年人失明的主要原因），也很重要。所以修理它很重要。 [Note: In neurodegeneration the main aggregates tend to form in other parts of the cell than the lysosome, but there is good evidence that this is a compensatory measure when neurons' lysosomes stop working properly as a result of the more modest accumulation of lysosomal toxins, so if we fix the lysosome then the non-lysosomal aggregates should disappear naturally.] [附注：在神经性退化中，主要的堆积物往往在细胞的其他部分形成、而不是在溶酶体形成，但有很好的证据表明，这是一种补偿措施：当神经原的溶酶体因溶酶体毒素积累到一定程度就停止工作，所以，如果我们修理了溶酶体，那么非溶酶体的堆积物就会自然消失。] So what's the solution? The most promising approach, in my view, is to enable cells to break the junk down in situ so that they don't fill up after all. 那么怎样解决？按我的观点，最有前途的方法是使细胞在原位降解垃圾，使它们最终不会充塞。 This can be accomplished by giving the cells extra enzymes that can degrade the relevant material. The natural place to seek such enzymes is in soil bacteria and fungi, as these aggregates, despite not being degraded in mammals, do not accumulate in soil in which animal carcasses are decaying, nor in graveyards where humans are decaying. 完成这项工作的办法，是给予细胞以能够降解相应物质的额外酶。寻找这些酶的自然地方是土壤细菌和真菌，因为这些聚集物，尽管不能在哺乳动物中被降解，但不会积累在动物尸体腐朽的土壤中，也不会积累在人类腐尸的墓地中。 Preliminary work in my department in Cambridge has already confirmed this optimism. The concept is a logical extension of the replacement of a natural lysosomal enzyme in people who are congenitally deficient for it, something that is already being done. Such deficiencies cause lysosomal storage disorders, such as Gaucher's disease, and replacement of the gene is an effective treatment. 在剑桥我系的预备实验，已经证实了这种乐观主义。这个理念是病人天生缺陷的天然溶酶体酶置换的逻辑延伸，在这方面已经做了一些事情。这样的缺陷引起溶酶体堆积病（例如，高歇病），基因置换是一种有效的疗法。 Gene therapy is still in its infancy, and its difficulty must not be underestimated, but progress is steady; it may not be overoptimistic to predict that by the time we have identified enzymes capable of degrading lysosomal junk and made them work in mice, gene therapy will be sufficiently advanced to allow their use in humans. 基因疗法仍然处在孩提时期，它的困难不应被低估，但是，正在逐步取得进展；以下的预言可能不会太过乐观：当我们能鉴定出可以降解溶酶体垃圾的酶、并使它们在小鼠中起作用之时，就是基因疗法足够先进、能允许它们应用于人类之日。 Also, very importantly, the biggest application of this technology doesn't need gene therapy at all, because the cells that need to be given the microbial genes are macrophages, special white blood cells, which come from the bone marrow. So we can make the necessary changes to blood stem cells in the laboratory, and then give them to people as a bone marrow transplant, which is much, much easier than gene therapy. 再者，非常重要的是，这项技术的最大应用，完全不需要基因疗法，因为需要给予微生物基因的细胞，是来自骨髓的巨噬细胞（特殊的白血细胞）。这样，我们可以在实验室中对血液干细胞进行必要的改变，然后把它们作为骨髓移植物输送给人们，这比基因疗法要容易得多。 We need a lot more work on this project. It will take time to find the right enzymes in the soil microorganisms, to find the ones that work well in mammalian cells and are not toxic, to modify them so that the cell knows how to target them to the lysosome, and so on. This is a project that is very "parallelisable" -- if lots and lots of laboratories work on it, it will succeed sooner. Enthusiasm for it is growing, as demonstrated by the calibre of the fourth SENS roundtable, a meeting focused on it which I ran in July 2004. 我们需要对这个项目进行大量工作。需要时间在土壤微生物中发现需要的酶、这些酶能在哺乳动物细胞中工作得很好而又没有毒性、修饰它们使得细胞知道怎样把它们运送到溶酶体，等等。这是一个"并连"的项目Ñ如果很多实验室同时开展研究，它就会成功得更快。这方面的积极性正在增大，正如第四次SENS圆桌会议的规模所表明的那样（这次会议是我于2004年7月举办的，聚焦于这个项目）。 Talks on this topic at IABG 10: 在IABG 10上以这个题目讲话：Archer Aubrey de Grey's publications on this topic Aubrey de Grey以这个题目发表文章：Aubrey de Grey's publications on this topic |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Problems or questions regarding this site should be directed to Dr. de Grey
有关本网站的问题和询问一律由Dr. de Grey主持。