2009年 08月 17日 07:14
Can A Tiny Fish Save Your Ears?
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.'
非 營利組織改善聽力協會(Better Hearing Institute)的一項調查表明﹐大約每10個美國人中就有一人患有聽力障礙。到目前為止﹐聽力喪失最常見的原因就是內耳中所謂的“毛細胞”受到損害 或者僅僅是因為上了年紀。過量的噪音以及某些疾病和藥物會損害毛細胞。問題的症結在於毛細胞一旦死亡﹐人類（像其他哺乳動物一樣）不能再生出新的毛細胞。
近 年來﹐華盛頓大學西雅圖分校的一個研究團隊一直在對一種水族館里常見的觀賞魚類──斑馬魚進行研究﹐試圖解決人類聽力喪失的問題。和許多其他水生生物一樣 ﹐斑馬魚在身體表面長有毛細胞。這些毛細胞的作用是探測水中的振動﹐其原理與人類內耳中的毛細胞相似。但是﹐與人類不同的是﹐斑馬魚的毛細胞在受損後還可 以再生。研究人員希望他們的工作可以揭開謎底﹐保護人類的毛細胞免受損傷、並推動毛細胞的再生。
內耳中的這種細胞是人類聽覺不可或缺的一 環。之所以稱為“毛細胞”﹐是因為它們在顯微鏡下看上去就像是在細胞外長出了絨毛。這些細細的絨毛﹐或者說纖毛﹐會因為聲波進入耳朵以後產生的振動而擺 動。這種運動會讓毛細胞產生出一種能夠經由聽覺神經傳給大腦的電信號。像助聽器和人工耳蝸等設備都有助聽效果﹐但都無法讓人們的聽力恢復到正常水平。助聽 器能夠增加聲音的強度﹐而人工耳蝸則會直接刺激聽覺神經。
上世紀80年代中期以前﹐研 究人員認為毛細胞無法在包括人類在內的溫血脊椎動物的體內再生。後來﹐美國的研究人員開始注意到﹐鳥類的聽力在因噪音或藥物受損後﹐它們的毛細胞會重新再 生出來。研究者們還認定﹐毛細胞再生可以提高聽力。實驗發現﹐新長出毛細胞的鳴禽可以重新以完美的音調唱出它們從前的歌曲。
但是﹐沒有跡 象表明哺乳動物的毛細胞可以再生。此外﹐即便在同一物種中﹐為什麼某些動物的毛細胞更容易死亡﹐而某些動物的毛細胞卻生命力更頑強﹐這仍舊是一個謎。“這 些年來﹐我真的甚至在走路的時候都在思索為什麼會有這個不同﹐”聽力科學教授埃德•魯貝爾(Ed Rubel)說。魯貝爾負責領導華盛頓大學科研項目的一部分工作。
促 進毛細胞再生主要有兩種辦法。有些研究組織正在試圖將幹細胞──一種未特化的細胞﹐它可以特化出其它類型細胞──培育成為毛細胞。方法是將它們從身體的其 它部位移植﹐或者促使內耳里自然生長的幹細胞發生轉變﹐特化為毛細胞。阿爾伯特•埃奇(Albert Edge)是哈佛大學醫學院(Harvard Medical School)的副教授﹐也是麻省醫院眼耳科(Massachusetts Eye and Ear Infirmary)的研究人員。埃奇表示﹐他的團隊已經能夠在實驗室中將老鼠的幹細胞分化成毛細胞﹐但是現在還不清楚這些細胞是否能夠正常工作。
而 華盛頓大學等組織的其他研究人員則將注意力集中在同毛細胞再生有關的分子和遺傳學原理﹐以及如何在毛細胞無法再生的動物身上重復這一過程上面。科學家說﹐ 這類研究的某些成果有可能最先應用在人類身上。一條令人鼓舞的消息是﹐魯貝爾已經和華盛頓大學另一名科學家大衛•雷布爾(David Raible)一起合作識別出了能夠保護毛細胞不受損害的化學物質。在他們的實驗中﹐斑馬魚身上活的毛細胞被染色。然後﹐研究人員在一個盤子上的96個淺 孔中放上一至兩條斑馬魚──實驗室使用的小斑馬魚僅有1/8英寸長。可能會對毛細胞起到保護作用的不同的化學物質被施用於每一個淺孔中。
去 年﹐他們的實驗室合作識別出了幾個似乎可以保護毛細胞的突變基因和類藥性混合物。他們的科研成果發表在《科學公共圖書館──遺傳學》(PLoS Genetics)雜志上。在2007年發表在《聽力研究》(Hearing Research)上的另一項研究中﹐他們確認了幾種對毛細胞有保護作用且已被美國食品和藥物管理局批准用作其他用途的藥物。不過﹐目前為止還沒有對人體 進行過試驗。
有 一項研究發現了一種似乎可以讓動物毛細胞再生的發育蛋白。在研究中﹐一名團隊成員發現了小雞的毛細胞受損後體內一種蛋白質的含量（小雞的毛細胞可以再生） 有所上升。但是﹐在對老鼠進行的同樣的實驗中（老鼠的毛細胞不能再生）﹐該蛋白質的含量沒有上升﹐這意味著該蛋白質可能與毛細胞再生有關。
“ 助聽器是解決問題的一個權宜之計﹐”美國耳聾和其他溝通障礙研究所(National Institute on Deafness and Other Communication Disorders)聽力喪失再生和發展項目的負責人南希•弗里曼(Nancy Freeman)表示。
Shirley S. Wang