Newsletter No. 371

2 No. 371, 19.1.2011 试 想像要完成一幅数百万片的拼图,得花多少时间 和精力?中大李嘉诚医学讲座教授和化学病理学 讲座教授卢煜明带领的研究团队就完成了这样一项创举。 他们拼就的并非一般拼图,而是从孕妇血浆的脱氧核糖核 酸(DNA)中找出胎儿零碎的DNA分子,再拼出胎儿的基 因图谱,这幅拼图标志着无创性产前检测法的突破。 1997年,卢教授发现孕妇血 浆含有胎儿的DNA,这项发 现令他声名大噪。他继而开 发出崭新的唐氏综合症产前 检测法,避免了传统入侵式 检测法可能导致流产的危 险。他开创性的工作促成了 新一代无创检测法的出现, 但迄今为止,这些方法每次 只能针对一种疾病作检测。 2010年,他和他的研究团队 再下一城,首先证明母体血 浆含有胎儿的全部基因特 质。接下来就是要开发无创 的胚胎基因组扫瞄技术,这 是极度困难的事,因为在孕 妇血浆DNA中,胎儿的DNA 分子只占十分之一,而且非常零碎。要从这些散落的碎片 拼凑出胎儿的基因图谱,难度不下于完成一个百万片的拼 图。卢教授说:「更棘手的是,母体血浆内含有大量孕妇本 身的DNA分子,胎儿的DNA分子就像这茫茫浩瀚DNA海 洋中的一粟。情况好比拼拼图时,先掺入另一幅拼图的千 万片小块,然后才开始拼合原先的第一幅拼图。」 为完成这工作,卢教授领导的团队抽取了一名母亲的血浆 样本,完成近四十亿个DNA分子的排序,约相当于人类基 因组的六十五倍。接着,研究团队拼凑出胎儿分别遗传自 父亲和母亲的两组基因图谱,再把这两组基因图谱结合, 从而得出胎儿的基因图谱。在这项试验中,研究人员利用 图谱检测出,由于父亲的遗传,胎儿是乙型地中海贫血症 基因的携带者。 卢教授的团队利用母体血浆DNA排序技术,能从胎儿 的基因图谱透视各种遗传特质和基因变异情况。去年 12月8日号的生物医学权威期刊《科学 ‧ 转译医学》,以封 拼出生命的奥秘— 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. 面故事形式发表他们的发现。这项研究的突破在于:只需 分析从孕妇身上抽取的一个血液样本,就能追溯出胎儿的 整个基因组,并且只需一次检测,即能一举诊断出多种遗 传病。 卢教授现在所做的工作,为生命的奥秘描画了日益细致清 晰的图像,以便预防甚至治疗疾病。 利用母体血浆 重整胎儿基因图 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 卢煜明教授(前排中)与他的研究团队 Prof. Dennis Y.M. Lo (centre, front row) and his research team