20、Restoring hearing
Hair tonic
Feb 17th 2005 From The Economist print edition
Gene therapy may restore lost hearing and balance
EVOLUTION has provided people with an exquisitely sensitive system of hearing and balance—the inner ear. But that sensitivity comes at a price, for the inner ear is also the sensory system most susceptible to damage. Nearly one child in 1,000 is born profoundly deaf, and if you are lucky enough to live to be 80, you have a 50% chance of losing enough of your hearing on the way for normal conversation to be troublesome without a hearing aid.
Often, the reason is damage to specialised sensory cells known as hair cells. The hair-like cilia that give these cells their name act as transducers. They convert the vibrations of sound into electrical impulses that the nervous system can handle. But cilia are fragile. Loud noises, such as those produced by machinery and booming stereos, can knock them away. So can some infections, such as meningitis. And so can some antibiotics. This damage is, at the moment, irreversible. But if Yehoash Raphael of the University of Michigan and his colleagues have their way, that will not be true for much longer.
Over the past two decades, many of the genes required for ear development have been identified. One of the most important is called Math1. But it is active only in embryos. Dr Raphael wondered, therefore, whether it would be possible to turn it on in adults, and thus generate new cilia.
The adults in question were guinea pigs—both literally and metaphorically. (Despite the colloquial use of the name, experiments involving rodents more often use mice or rats.) They were treated with antibiotics, to kill their hair cells. This made them completely deaf. Then, after four days, their left ears were infected with an adenovirus (one of the sorts of virus that cause colds). Half the infections were with viruses that had had a Math1 gene engineered into them. Half used viruses that had had a dummy DNA sequence engineered in instead. The hope was that the Math1 gene would be activated in the infected cells, which would then grow cilia, thus becoming hair cells. And it worked. As Dr Raphael reports in Nature Medicine, eight weeks later the animals treated with Math1-carrying adenovirus had regenerated their hair cells and were able to hear.
Their hearing was not restored completely. Although they were able to perceive sounds in the range of 40-50 decibels—similar to the volume of a typical conversation—Dr Raphael suspects that what they heard was rather fuzzy. That is because the treatment only caused the regrowth of a group of cells called the inner hair cells. These determine the threshold of hearing. A second group, the outer hair cells, did not reappear. The outer cells are responsible for amplifying sound, and for modulating its quality. Dr Raphael suspects that a second gene will need to be added to the viral package to stimulate the outer cells’ regrowth.
Meanwhile, at the University of Maryland, Hinrich Staecker has been doing similar experiments designed to restore balance in mice. In these experiments, which have yet to be published, he uses an antibiotic injection to knock out the hair cells devoted to balance. (These cells work by detecting movements in the fluid that fills the canals of the inner ear.) Forty-eight hours later, he injects the animals with adenoviruses containing Math1 genes. A month after the injection, the animals have regained their sense of balance.
Both groups of researchers think this is the beginning of a new approach to treating inner-ear problems. Dr Staecker predicts that the first Math1 gene-therapy trials will happen in people who have lost their sense of balance. If those work, hair cell-regeneration treatments for deafness may follow. There is still a long way to go. Trials of any kind are probably five years away. But it looks as if science is having more luck restoring the hairs of the ears to youthful vigour than it is with the hairs of the head.
20、进化给了人类感觉敏锐的听觉和平衡系统 — 内耳。但这种灵敏的感觉实在得来不易，因为内耳也是最易受到损伤的感官系统。差不多每 1000 个孩子中就有 1 个是先天的深度耳聋，如果你有幸能活到 80 岁，那么你就有 50% 的可能会在不借助助听器时很难进行正常的谈话。
通常认为原因是特殊感觉器官毛细胞受到了损伤。毛细胞得名于其像头发丝儿一样的纤毛，这些纤毛起到的作用就像是传感器。它们将声音的振动转化为神经系统可以感知的电波。然而纤毛也是很脆弱的。机器轰鸣和高声音响等噪声喧哗就能轻易将其破坏。某些传染病，比如脑膜炎，也会损伤毛细胞。同样，有些抗生素也会伤害毛细胞。目前，这种损伤还是不可治愈的。不过，如果密执安大学的 Yehoash Raphael 和他的同事们能够成功，这种情况就不会持续太久了。
在过去的二十年里，耳部研究需要的许多基因都得到了发现。其中最重要的之一称作 Math1 。可是它仅仅在晶胚中才具有活性。因此 Dr Raphael 想知道是否可以给成年个体移植，并由此再生出新的纤毛细胞。
这里所讨论的成年个体是指豚鼠 — 字面意义和引申含义都是如此。(除了口语通俗说法以外，实验所用啮齿类动物往往是小鼠或大鼠。)给它们施加抗生素来杀死毛细胞，使其完全耳聋。四天以后，另一只不聋的耳朵也被一种腺病毒所感染(引起感冒的一种病毒)。受感染老鼠中一半携带有植入 Math1 基因的病毒。一半携带有植入虚拟 DNA 序列的病毒。寄希望于 Math1 基因能够在受感染的细胞中存活，产生纤毛，进而成为毛细胞。真的起作用了。据 Dr Raphael 在 Nature Medicine 上的报告， 8 周以后，携带 Math1 腺病毒的动物再生了毛细胞并且恢复了听力。
老鼠们的听力并没有完全恢复。尽管它们能察觉到 40~50 分贝范围内的声音 — 接近于正常谈话的音量 —Dr Raphael 还是怀疑老鼠们听到的声音有些失真。因为治疗仅仅引起了称为内耳毛细胞的细胞群的再生长。这些只是决定听觉的开始。第二个细胞群，外耳细胞群并没有再现。外耳细胞司职放大声音并调节声音的质量。 Dr Raphael 怀疑还有另一个基因需要加入病毒包来刺激外耳细胞的再生。
同时，在马里兰大学， Hinrich Staecher 也作着类似的实验，旨在恢复小鼠的平衡感。他在这些尚在整理出版的试验中，使用了一种抗生素注射剂来破坏保持平衡的毛细胞。(这些细胞通过探测充满内耳道的液体的移动来发挥功能。) 48 小时以后，他给老鼠们注射含有 Math1 基因的腺病毒。经过 1 个月的注射，老鼠竟重新有了平衡感。
两组研究人员都认为这是治疗内耳疾病新尝试的一个开端。 Dr Staecker 预言首例用于人类失去平衡感的 Math1 基因疗法试验即将进行。如果奏效了，毛细胞再生治疗耳聋可能随之而来。当然，道路还是漫长而曲折的。任何类型的实验可能都要有 5 年之遥。但是看来好像科学在恢复毛细胞使耳朵返老还童方面比起其对头上的头发所做的努力要更加成功。
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