Newsletter No. 371

2 No. 371, 19.1.2011 試 想像要完成一幅數百萬片的拼圖，得花多少時間 和精力？中大李嘉誠醫學講座教授和化學病理學 講座教授盧煜明帶領的研究團隊就完成了這樣一項創舉。 他們拼就的並非一般拼圖，而是從孕婦血漿的脫氧核糖核 酸（DNA）中找出胎兒零碎的DNA分子，再拼出胎兒的基 因圖譜，這幅拼圖標誌着無創性產前檢測法的突破。 1997年，盧教授發現孕婦血 漿含有胎兒的DNA，這項發 現令他聲名大噪。他繼而開 發出嶄新的唐氏綜合症產前 檢測法，避免了傳統入侵式 檢測法可能導致流產的危 險。他開創性的工作促成了 新一代無創檢測法的出現， 但迄今為止，這些方法每次 只能針對一種疾病作檢測。 2010年，他和他的研究團隊 再下一城，首先證明母體血 漿含有胎兒的全部基因特 質。接下來就是要開發無創 的胚胎基因組掃瞄技術，這 是極度困難的事，因為在孕 婦血漿DNA中，胎兒的DNA 分子只佔十分之一，而且非常零碎。要從這些散落的碎片 拼湊出胎兒的基因圖譜，難度不下於完成一個百萬片的拼 圖。盧教授說：「更棘手的是，母體血漿內含有大量孕婦本 身的DNA分子，胎兒的DNA分子就像這茫茫浩瀚DNA海 洋中的一粟。情況好比拼拼圖時，先摻入另一幅拼圖的千 萬片小塊，然後才開始拼合原先的第一幅拼圖。」 為完成這工作，盧教授領導的團隊抽取了一名母親的血漿 樣本，完成近四十億個DNA分子的排序，約相當於人類基 因組的六十五倍。接着，研究團隊拼湊出胎兒分別遺傳自 父親和母親的兩組基因圖譜，再把這兩組基因圖譜結合， 從而得出胎兒的基因圖譜。在這項試驗中，研究人員利用 圖譜檢測出，由於父親的遺傳，胎兒是乙型地中海貧血症 基因的攜帶者。 盧教授的團隊利用母體血漿DNA排序技術，能從胎兒 的基因圖譜透視各種遺傳特質和基因變異情況。去年 12月8日號的生物醫學權威期刊《科學 ‧ 轉譯醫學》，以封 拼出生命的奧秘— To Reveal the Mystery of Life— Decoding Fetal Genomic Map fromMaternal Blood so far these have been limited to screening one disease at a time. In 2010, he and his teammade a breakthrough by showing that the entire fetal genome is represented in maternal plasma. The next step of devising a non-invasive fetal genome scan was challenging, as fetal DNA molecules, which account for only about 10% of the DNA in the maternal plasma, are highly fragmented. Constructing the fetus’s genetic profile from these fragments would be tantamount to assembling a million-piece jigsaw puzzle. Professor Lo said, ‘To make matters worse, these fetal DNA molecules in the mother’s blood plasma are drifting in an ocean of maternal DNA molecules. This is like adding in tens of millions of pieces from another jigsaw puzzle and then trying to re-assemble the first one.’ To overcome this, the CUHK research team led by Professor Lo sequenced nearly four billion DNA fragments from a maternal blood sample, which was equivalent to some 65-fold coverage of the human genome. They then constructed separate genetic maps that the fetus had inherited from the father and from the mother. By combining the paternally-inherited and maternally-inherited genetic maps, CUHK researchers were able to arrive at a genomic map of the fetus. They then used this map to confirm that, in the test case in point, the fetus was a carrier of beta-thalassaemia from the father’s side. By carefully sequencing the maternal plasma DNA, Professor Lo’s team has been able to reveal the genome- wide genetic and mutational profile of the fetus. Their findings were published as the cover story in the 8 December issue of Science Translational Medicine , a prestigious interdisciplinary biomedical journal. The implication of this ground-breaking research is that by analysing a blood sample from the pregnant woman the entire genome of the fetus can be deduced and screened for many possible genetic disorders in one go. What Professor Lo is doing is to reveal the mystery of life in ever-increasing detail which will enhance prevention and even treatment. 面故事形式發表他們的發現。這項研究的突破在於：只需 分析從孕婦身上抽取的一個血液樣本，就能追溯出胎兒的 整個基因組，並且只需一次檢測，即能一舉診斷出多種遺 傳病。 盧教授現在所做的工作，為生命的奧秘描畫了日益細緻清 晰的圖像，以便預防甚至治療疾病。 利用母體血漿 重整胎兒基因圖 I magine how difficult it must be to assemble a complex jigsaw puzzle of seemingly infinite pieces? Prof. Dennis Y.M. Lo, Li Ka Shing Professor of Medicine and Professor of Chemical Pathology at CUHK, and his research team have succeeded in completing this unprecedented and arduous task. What they constructed was no ordinary puzzle, but something that signified a breakthrough in the medical field—the fetal genomic profile, and they did it by finding highly fragmented fetal DNA molecules in maternal plasma. In 1997, Professor Lo made a splash by discovering that the DNA of an unborn fetus could be found in the blood plasma of its pregnant mother. He went on to develop a new method for the prenatal diagnosis of Down’s syndrome which averted the risk of miscarriage inherent in traditional invasive methods. His pioneering work has made possible a new generation of non-invasive tests but 盧煜明教授（前排中）與他的研究團隊 Prof. Dennis Y.M. Lo (centre, front row) and his research team