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一条小鱼可以拯救你的听力?

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For many people, loss of hearing is irreversible.

For scientists trying to figure out what can be done about that, one answer may lie -- or swim, actually -- in freshwater aquariums.

About one of every 10 Americans suffers from hearing impairment, according to a survey conducted by the Better Hearing Institute, a nonprofit advocacy group. By far the most common cause of hearing loss is damage to the so-called hair cells in the inner ear as a result of excessive noise, certain illnesses and drugs, and simple aging. The problem is that once hair cells die, humans (like other mammals) aren't able to grow new ones.

In recent years, a research team at the University of Washington in Seattle has been working on finding a way to resolve that problem in experiments involving the zebrafish, a common aquarium denizen. The zebrafish, like many aquatic creatures, has clusters of hair cells running along the outside of its body that help sense vibrations in the water, working in a similar way to hair cells in the human inner ear. But unlike humans, zebrafish are able to regenerate their damaged hair cells. Researchers hope their work can unlock secrets to protect human hair cells from becoming damaged and to stimulate the cells to regenerate.

Hair cells, which took their name because under the microscope they look like cells with little hairs growing out of them, are an essential link in hearing. The filament hairs, or cilia, bend with vibrations caused by sound waves entering the ear. That induces the hair cell to create an electrical signal that is passed on to the auditory nerve and sent to the brain. Devices such as hearing aids, which amplify sounds, and cochlear implants, which stimulate the auditory nerve directly, help people hear, but neither restores hearing to normal.

Until the mid-1980s, researchers thought warm-blooded vertebrates, including humans, weren't able to regenerate hair cells. Then, researchers around the country began observing that hair cells grew back in birds whose hearing was damaged either by noise or drugs. They also determined that hair-cell regeneration can result in improved hearing; in experiments, song birds that had grown new hair cells were able to resume singing their original songs with perfect pitch again.

But there is no indication that mammals can regenerate hair cells. And why some animals, even within the same species, are more vulnerable to hair-cell death, while others are more resistant to it, is a mystery. 'I literally walked around for years wondering about this variability,' says Ed Rubel, a professor of hearing sciences who leads part of the University of Washington research effort.

There are two main approaches to efforts aimed at inducing hair cells to regenerate. Some research groups are attempting to get stem cells -- undifferentiated cells that can develop into various specialized cells -- to turn into hair cells, either by transplanting them from other parts of the body, or by stimulating stem cells naturally occurring in the inner ear to transform themselves. Albert Edge, an associate professor at Harvard Medical School and a researcher at the Massachusetts Eye and Ear Infirmary, says his team has been able to turn mouse stem cells into hair cells in a laboratory dish, though it isn't clear whether those cells are functional or not.

Other researchers, like those at the University of Washington, are focused on understanding the molecules and genetics involved with hair-cell regeneration, and how to mimic this process in animals that don't spontaneously regenerate hair cells. Scientists say aspects of such research, likely will be the first to have applications in humans. One encouraging angle: Dr. Rubel, in collaboration with another University of Washington scientist, David Raible, has identified chemicals that seem to protect hair cells from damage. In this experiment, zebrafish are exposed to a dye that highlights living hair cells. Then, one or two of the zebrafish -- the young ones used in the lab measure just 1/8 of an inch long -- are placed in each of 96 shallow holes contained on a plate. Different chemicals are administered to each fish group that might confer protection to the hair cells.

Finally, another chemical known to kill the fish hair cells is added. Under a microscope, researchers then examine the fish to look for cases where the dye is still evident, signaling that the cells are still alive and suggesting that the protective chemical appears to have done its job.

Those chemicals found to confer protection on fish hair cells are currently also being tested on mice and rats. The idea is that, once a drug is discovered that effectively protects hair cells from dying and is safe for humans, the medicine could be used to help protect the hearing of patients receiving drugs known for killing hair cells, like chemotherapeutic agents.

Dr. Rubel's and Dr. Raible's teams also are studying the genetics of zebrafish to identify markers that confer hair-cell protection.

Last year, their labs jointly identified several genetic mutations and drug-like compounds that seemed to protect hair cells from death, publishing their findings in the journal PLoS Genetics. In a separate study, published in 2007 in Hearing Research, they identified several drugs that also appear to be protective and were already approved for other purposes by the Food and Drug Administration. No tests have been performed on humans, however.

The teams also are working on a separate group of studies to understand the genes and other molecules that allow the regeneration of hair cells in zebrafish, birds and mice.

Surrounding cells known as support cells can both turn into hair cells or generate new hair cells. Dr. Rubel's lab is investigating both processes. 'If we understand the template of genes that are expressed by the cells we would want to divide, then we could tap into that template' to mimic regeneration efforts in mammals, he says.

One finding identified a developmental protein that appears to be turned on in animals able to regenerate hair cells. In one study, a team member found a type of protein increased in a chick (which can regenerate hair cells) after its cells were damaged. But in running the same experiment in a mouse (which can't regenerate hair cells), the protein didn't increase, suggesting the protein could be involved in regeneration.

Scientists involved in the experiments say there could be therapeutic trials to prevent hearing loss using drugs within a decade. However, finding a cure for hearing loss using hair-cell regeneration is likely to be at least 20 years away, they say.

'Hearing aids are Band-aids on a problem that already exists,' says Nancy Freeman, director of the regenerative and development program in hearing loss at the National Institute on Deafness and Other Communication Disorders.

'The hope with this type of [regeneration] approach is that at the end of the day you'd end up with something that natively restores function.'

对许多人来讲,听力的丧失是一件无法挽回的事。

对致力于研究这一问题的科学家来说,避免听力丧失的一个办法可以在淡水水族馆里找到。

在放大2.1万倍的照片中可以清楚的看到耳蜗内的“毛细胞”非营利组织改善听力协会(Better Hearing Institute)的一项调查表明,大约每10个美国人中就有一人患有听力障碍。到目前为止,听力丧失最常见的原因就是内耳中所谓的“毛细胞”受到损害或者仅仅是因为上了年纪。过量的噪音以及某些疾病和药物会损害毛细胞。问题的症结在于毛细胞一旦死亡,人类(像其他哺乳动物一样)不能再生出新的毛细胞。

近年来,华盛顿大学西雅图分校的一个研究团队一直在对一种水族馆里常见的观赏鱼类──斑马鱼进行研究,试图解决人类听力丧失的问题。和许多其他水生生物一样,斑马鱼在身体表面长有毛细胞。这些毛细胞的作用是探测水中的振动,其原理与人类内耳中的毛细胞相似。但是,与人类不同的是,斑马鱼的毛细胞在受损后还可以再生。研究人员希望他们的工作可以揭开谜底,保护人类的毛细胞免受损伤、并推动毛细胞的再生。

内耳中的这种细胞是人类听觉不可或缺的一环。之所以称为“毛细胞”,是因为它们在显微镜下看上去就像是在细胞外长出了绒毛。这些细细的绒毛,或者说纤毛,会因为声波进入耳朵以后产生的振动而摆动。这种运动会让毛细胞产生出一种能够经由听觉神经传给大脑的电信号。像助听器和人工耳蜗等设备都有助听效果,但都无法让人们的听力恢复到正常水平。助听器能够增加声音的强度,而人工耳蜗则会直接刺激听觉神经。

上世纪80年代中期以前,研究人员认为毛细胞无法在包括人类在内的温血脊椎动物的体内再生。后来,美国的研究人员开始注意到,鸟类的听力在因噪音或药物受损后,它们的毛细胞会重新再生出来。研究者们还认定,毛细胞再生可以提高听力。实验发现,新长出毛细胞的鸣禽可以重新以完美的音调唱出它们从前的歌曲。

但是,没有迹象表明哺乳动物的毛细胞可以再生。此外,即便在同一物种中,为什么某些动物的毛细胞更容易死亡,而某些动物的毛细胞却生命力更顽强,这仍旧是一个谜。“这些年来,我真的甚至在走路的时候都在思索为什么会有这个不同,”听力科学教授埃德•鲁贝尔(Ed Rubel)说。鲁贝尔负责领导华盛顿大学科研项目的一部分工作。

促进毛细胞再生主要有两种办法。有些研究组织正在试图将干细胞──一种未特化的细胞,它可以特化出其它类型细胞──培育成为毛细胞。方法是将它们从身体的其它部位移植,或者促使内耳里自然生长的干细胞发生转变,特化为毛细胞。阿尔伯特•埃奇(Albert Edge)是哈佛大学医学院(Harvard Medical School)的副教授,也是麻省医院眼耳科(Massachusetts Eye and Ear Infirmary)的研究人员。埃奇表示,他的团队已经能够在实验室中将老鼠的干细胞分化成毛细胞,但是现在还不清楚这些细胞是否能够正常工作。

而华盛顿大学等组织的其他研究人员则将注意力集中在同毛细胞再生有关的分子和遗传学原理,以及如何在毛细胞无法再生的动物身上重复这一过程上面。科学家说,这类研究的某些成果有可能最先应用在人类身上。一条令人鼓舞的消息是,鲁贝尔已经和华盛顿大学另一名科学家大卫•雷布尔(David Raible)一起合作识别出了能够保护毛细胞不受损害的化学物质。在他们的实验中,斑马鱼身上活的毛细胞被染色。然后,研究人员在一个盘子上的96个浅孔中放上一至两条斑马鱼──实验室使用的小斑马鱼仅有1/8英寸长。可能会对毛细胞起到保护作用的不同的化学物质被施用于每一个浅孔中。

最后,他们再向浅孔中加入一种能够杀死鱼类毛细胞的化学物质。在显微镜下,研究人员仔细观察,寻找染液颜色依然鲜亮的斑马鱼,因为这标志着它们的毛细胞还活着,意味着起保护作用的化学物质看上去完成了它的任务。

研究人员目前还在老鼠身上试验那些对鱼类毛细胞有保护作用的化学物质。科学家们认为,一旦一种药物被发现可以有效保护毛细胞,而且使用起来对人类是安全的,这种药物就可以用来帮助保护病人们的听力──他们接受的药物治疗,如化疗药物,能将毛细胞杀死。

鲁贝尔和雷布尔的团队也在研究斑马鱼的遗传基因,以识别对毛细胞有保护作用的基因标记。

去年,他们的实验室合作识别出了几个似乎可以保护毛细胞的突变基因和类药性混合物。他们的科研成果发表在《科学公共图书馆──遗传学》(PLoS Genetics)杂志上。在2007年发表在《听力研究》(Hearing Research)上的另一项研究中,他们确认了几种对毛细胞有保护作用且已被美国食品和药物管理局批准用作其他用途的药物。不过,目前为止还没有对人体进行过试验。

他们的团队同时还在进行另一组研究,试图了解导致斑马鱼、鸟类和老鼠的毛细胞再生的基因和其他分子。

毛细胞周围的细胞被称为“支持细胞”,它们可以转化成毛细胞或者产生新的毛细胞。鲁贝尔的实验室正在研究这两个进程。“如果我们理解了这种细胞的基因模板,那么我们就可以利用这个模板在哺乳动物身上模拟毛细胞再生,”他说。

有一项研究发现了一种似乎可以让动物毛细胞再生的发育蛋白。在研究中,一名团队成员发现了小鸡的毛细胞受损后体内一种蛋白质的含量(小鸡的毛细胞可以再生)有所上升。但是,在对老鼠进行的同样的实验中(老鼠的毛细胞不能再生),该蛋白质的含量没有上升,这意味着该蛋白质可能与毛细胞再生有关。

参与这些实验的科学家们说,使用药物防止听力丧失的临床实验有可能会在十年内实现。但是,找到利用毛细胞再生治疗听力丧失的办法可能还需要至少20年的时间。

“助听器是解决问题的一个权宜之计,”美国耳聋和其他沟通障碍研究所(National Institute on Deafness and Other Communication Disorders)听力丧失再生和发展项目的负责人南希•弗里曼(Nancy Freeman)表示。

“利用这种(促进毛细胞再生的)方法,我们希望有朝一日可以找到一种方法让听力能够自然地得到恢复。”
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