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  • 學者?學生

    姚凱:為失明者尋找“光明之路”

    發布者:新聞中心發布時間:2019-01-06瀏覽次數:1962

    記者   程毓

      姚凱,生命科學與健康學院副教授,湖北省“楚天學子”,長期從事神經生物學與干細胞生物學的研究。 

      “沒有活細胞”“還是沒有活細胞”……一次,又一次,姚凱從顯微鏡里看到“殘酷”的結果。生命科學與健康學院的青年學者姚凱干了20年神經生物學,深深地體會到“在生物學研究里,90%都是失敗”。

      今年,研究終于取得重大突破,“運用干細胞療法讓先天性眼盲的小鼠首次見到光明”的研究成果以姚凱為第一作者,8月底發表在國際頂級學術期刊《Nature(自然)》正刊上,立即引起了廣泛的關注。

      美國眼科研究所的著名神經生物學家Anand Swaroop、東京大學分子和發育生物學家Sumiko Watanabe等業界專家均表示,此項研究為干細胞治療和基因治療領域的突破性成果,特別是在利用內源性干細胞治療遺傳性疾病方面做出了創造性發展。

      姚凱的研究成果有望讓全球上億失明者見到光明。新華社、中國新聞網等多家媒體相繼報道。 

    要為失明者尋找“光明之路” 

      神經系統,是人體內最復雜、最神秘的結構。有人說,相比大腦及其神經組織,人體的其它器官簡單得簡直不值一提。大腦的神秘,讓少年時的姚凱為之癡迷。

      每天放學路過報刊亭,只要看到新一期的《奧秘》《探索》雜志,他就趕緊買回來,全神貫注地看雜志,可以幾個小時不挪屁股。

      中學時,學習很緊張,他借來《夢的解析》當消遣書。“一知半解,但是越看不懂,就越想看。”姚凱沉醉其中。研究大腦神經,成了他少年時懷揣的夢想。

    2011年,姚凱成功申請進入美國耶魯大學進行博士后研究,專攻神經細胞的損傷與再生機制。兒時的夢想終于變成了現實,欣喜的他也深知,這條科研之路必然充滿了艱辛。

      每天翻閱文獻,大量泛讀相關文章,兩個多月他閱讀了兩百多本學術期刊,挑選出的重要文獻打印后摞起來比1.75米的他還高出許多。

      他了解到,全球有上億人患神經退行性疾病而造成視力損傷并最終致盲,臨床上尚無有效的治療手段。看不到美麗的世界,生活有諸多不便,想到失明者的痛苦,姚凱產生了強烈的責任感,“要為失明者尋找‘光明之路’”。

      文獻顯示,人類和哺乳動物眼體里的感光細胞一旦死亡,無法自主再生,結果就是失明。“當時最新的研究成果是通過大量損傷視網膜神經細胞,激活Müller細胞——視網膜內的神經膠質細胞,負責支持、滋養周圍的神經元。然而,神經細胞再生效果非常不理想,或者說幾乎為零。”

      姚凱想,能否在不損傷視網膜的情形下,激活Müller細胞呢?查閱文獻得知,自2006年之后,這個領域已長達5年沒有任何突破性進展。

      沒有資料借鑒,前景一片未知。“未知的領域,更吸引我去探索。”姚凱的基因似乎就是這樣的。制定了詳細的實驗計劃后,他一頭埋進了實驗室。

      為了激活Müller細胞,需要制作攜帶有特定轉基因的病毒,其滴度還要達到每毫升濃縮液包含1013個以上的病毒顆粒。

      培養溫度不合適,病毒就失去了活性;病毒含量少了,又發揮不了激活的作用。通過半年的反復摸索,病毒含量與活性終于穩定到了標準值。

      然而,這才是剛剛開始。 

    5年的艱辛研究歷程 

      進入實驗的第一步——激活Müller細胞。

      姚凱將培養的有效、無毒病毒,注射入先天性失明的小鼠眼睛里。幾周后,在顯微鏡下觀察,細胞沒有任何激活的跡象。

      是注射技術問題嗎?

      眼睛里的血管又細又脆,而且密密麻麻,注射時碰到血管極易造成眼體出血就意味著失敗。而小鼠只有半個拳頭大,眼睛更是只有綠豆般大小,注射的難度可想而知。

      握著針筒,屏住呼吸,姚凱目不轉睛地在顯微鏡下尋找血管的縫隙,輕輕地進入,注射后又輕輕地抽出。

      這樣的動作,姚凱每天忙完其它工作后,從中午做到傍晚,整整做了一個多月,手臂酸痛得抬不起來。為了增強臂力,他每天舉啞鈴。

      他的技術提高了,實驗用的小鼠安靜得幾乎感覺不到被注射。顯微鏡下,也出現了激活的Müller細胞。

      進入實驗的第二步——轉化感光細胞。

      蛋白質具有轉化細胞的能力。人體內有10萬種以上的蛋白質,如何從中挑選出所需的轉錄因子?又一次經過海量的閱讀與數周的論證,10種蛋白質被選作實驗。

      如何找到最佳的組合?姚凱從1個蛋白質做起,把10個蛋白質分別注射入小鼠眼體里,然后等待一個月后觀察結果。接著,做2個蛋白質的各種組合,3個蛋白質的各種組合……

      “需要做的實驗數量太龐大了,那時候不敢去想象什么時候是個盡頭。”姚凱只能埋頭做。

      日復一日地從事緊張而枯燥的實驗,難免感到苦悶,姚凱就跑上十幾圈,直到渾身大汗淋漓,平復波動的情緒。

      歷經一年多,實驗結果顯示,有3種蛋白質的組合效果最為明顯。

      調整病毒的劑量,優化時間的間隔……干細胞療法的效果漸漸明顯,從隱隱約約地看得到數個轉化的新的神經細胞,逐漸出現成片成片的神經細胞。

      對小鼠的大腦活動測量終于顯示:這些新生神經元成功地整合到視覺通路中,并將光信號傳遞給了大腦視覺皮層,先天性眼盲的小鼠產生了視覺反應。

      《自然》雜志兩位評委高度評價這一研究成果,“這項工作極其重要,把Müller細胞誘導為新的神經細胞,以前在哺乳動物中從未發生過。”“這項成果已經在神經生物學領域走得非常遠了。”

      “祝賀你成功了!”同行們紛紛向姚凱表示祝賀。他靦腆地說,“我比較幸運。”

    5年的艱辛付出,在姚凱的實驗室里隨處可見。靠墻的柜子里,每天記錄各種數據的A4本子,已有厚厚的幾十本,占滿了整整一層。 

    努力工作,永遠是正確的 

      “不亦樂乎”,是姚凱的QQ昵稱。

      “從事科研工作,不能總想著結果會怎樣,要享受科研的過程,否則難以堅持到成功。”他翻開《自然》期刊,指著刊發的論文說:“為了得到這4張圖,共有5個團隊參與,失敗了成千上萬次。”

      從少年的憧憬,到青年的追逐,到現在的淡定,姚凱一直有著對科研的執著和堅守,也收獲了一份份回報。

      在香港中文大學讀博士期間,姚凱發表了5篇有分量的論文。美國耶魯大學的著名神經生物學專家陳波教授收到他的博士后申請郵件有點“動心”,當天回了郵件:“把你導師的名字和聯系電話發給我。”

      不要推薦信,不聽自薦詞,陳教授直接致電姚凱的博士導師。一番交流后,第二天就“越洋”電話給姚凱。“你的導師對你的評價很高,歡迎你來美國和我們一起從事神經生物學研究。”

      從發郵件,到獲得前往美國的offer,前后僅三天。更為驚喜的是,來到美國后得知,師爺是視覺生物學領域的世界級“泰斗”——美國科學院院士、世界頂尖的霍華德·休斯研究所特聘研究員Constance Cepko。這位師爺的弟子現在不少是這個領域的“小泰斗”,師兄們的名字在《自然》《科學》等世界頂級學術期刊頻頻“亮相”。

      師門弟子間經常性的學術交流,讓姚凱“腦洞打開”,研究成果也不斷涌現。他利用病毒將β-Catenin基因轉入小白鼠視網膜中,在視網膜不受損的狀態下激活神經干細胞。該發現在國際上尚屬首次,為臨床上治療視網膜神經退行性疾病提供了實驗基礎。該研究成果以姚凱為第一作者,2016年9月發表在國際頂級期刊《Cell(細胞)》子刊上。

      不到40歲的他前后發表了10多篇高水平的論文,受邀成為近20種SCI雜志的審稿專家。

      我校生命科學與健康學院院長張同存談起“80”后的姚凱,贊賞之情溢于言表:“姚凱嚴謹、執著,對研究充滿了熱愛。他還會出更多的標志性成績。”

    對于姚凱,每一天的工作都是一場有趣的考試。“今天沒考好,不要在意。”他始終堅信,“努力工作,永遠是正確的。”


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