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约翰·戈登John B. Gurdon,山中伸弥Shinya Yamanaka - 2012年诺贝尔生理学或医学奖
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北京时间10月8日下午5点30分,2012年诺贝尔生理学或医学奖揭晓,英国科学家约翰·戈登(John B. Gurdon)和日本科学家山中伸弥(Shinya Yamanaka)获奖,获奖理由为“发现成熟细胞可被重编程变为多能性”。
 
John B. Gurdon,1933年出生于英国的Dippenhall。1960年他从牛津大学获得博士学位,曾在加州理工学院做博士后。他于1972年加入剑桥大学,成为细胞生物学教授。目前他供职于剑桥Gurdon研究所。
 
Shinya Yamanaka,1962年出生于日本大阪。1987年他从神户大学获得MD。在转向基础研究之前,他曾受训为整形外科医生。1993年他从大阪市立大学获得博士学位,之后他曾供职于美国旧金山Gladstone研究所和日本奈良先端科学技术大学院大学。目前他于日本京都大学担任教授。
 
今年的诺贝尔生理学或医学奖颁给两位发现“成熟、特化的细胞能够被重编程为可发育成身体组织的非成熟细胞”的科学家。他们的发现革新了我们对细胞和有机生命体发育的理解。
 
1962年,约翰·戈登发现细胞的特化(specialisation)是可逆转的。在一项经典实验中,他将一个青蛙卵细胞的细胞核替换为成熟肠细胞的细胞核。这个改变了的卵细胞发育成为一只正常的蝌蚪。该成熟细胞的DNA仍含有发育成青蛙所需的全部信息。
 
40多年后,山中伸弥在2006年发现了小鼠的完整成熟细胞是如何能够被重编程为非成熟干细胞。令人惊讶的是,通过导入仅仅少量的基因,就可以将成熟细胞重编程为多能干细胞,即可发育成为身体各种组织的非成熟细胞。
 
这两项突破性的发现彻底改变了我们对于发育和细胞特化的看法。现在,我们知道成熟细胞并不需要永远局限在它的特化功能里。历史被改写,新的研究领域产生。通过重编程人体细胞,疾病研究的新机遇获得实现,诊断与治疗的新方法获得发展。
 
生命——一次不断特化的旅程
 
我们所有人都是由受精卵细胞发育而来。在受精后的第一天里,这些组成胚胎的非成熟细胞,每一个都具有发育成成熟生命体中各种细胞类型的能力,这一类细胞被称为多能干细胞。随着胚胎的进一步发育,这些细胞发育成神经细胞、肌肉细胞、肝脏细胞以及其他各类细胞——每一种细胞都肩负起成熟身体内的一项特定使命。之前,这趟从非成熟细胞到特化细胞的旅程被认为是单一方向的。人们曾以为,细胞在成熟过程中是以这样的方式发生着改变,不可能回到非成熟、多能的阶段。
 
青蛙的逆发育
 
特化细胞功能的不可逆转一度被当成是教条,约翰·戈登向它发出挑战。他曾假设,细胞的基因组或许仍然含有其发育成生命体各种类型的细胞的所需要的全部信息。1962年,为了验证他的这种假设,他用蝌蚪肠道的成熟特化细胞的细胞核替换掉青蛙卵细胞的细胞核。该卵细胞发育成一只功能完全的克隆蝌蚪并最终长成如同实验培养出的成体青蛙。成熟细胞的细胞核并未丢失功能完全的生命体发育所需的能力。
 
戈登这次里程碑式的发现一开始是受到质疑的,但经过其他科学家的确认,人们接受了他的发现。这项发现引起研究热潮,相关技术获得进一步发展,最终发展到哺乳动物的克隆。戈登的研究告诉我们,一个成熟特化细胞的细胞核是可以被逆转到非成熟、多能化的状态。但是他的实验是将一些细胞的细胞核抽出,然后引入另外一些细胞的细胞核。有没有可能让一个完整的细胞回退到多能干细胞呢?
 
往返旅程——成熟细胞返回干细胞状态
 
在戈登的发现40余年后,山中伸弥在一项突破性的研究中回答了这个问题。他的研究有关胚胎干细胞,分离自胚胎并在实验室中培养的诱导多能干细胞。这些干细胞最初是由Martin Evans(2007年诺奖得主)从小鼠身上分离得到。山中伸弥试图发现保持它们未成熟的基因。当几个这样的基因被鉴别出来后,他进行了测试,以确定它们是否能够重编程成熟细胞变成多能干细胞。
 
山中伸弥与合作者用不同的组合方式向成熟细胞中引入了这些基因,这些成熟细胞来自于结缔组织和纤维原细胞。他们在显微镜下检测了结果,最终发现其中的一个组合起作用,而其“处方”是惊人的简单。通过同时引入四个基因,他们可以重编程纤维原细胞变成未成熟干细胞!
 
由此得到的诱导多能干细胞(iPS细胞)能够发育成多种成熟细胞,例如纤维原细胞、神经细胞以及肠细胞等。完整、成熟的细胞可被重编程成多能干细胞这一发现在2006年一经发表,立即被认为是一个重大的突破。
 
从惊人发现到医学应用
 
戈登和山中伸弥的发现显示,在某种情况下,特化的细胞能够回拨发育的时钟。虽然它们的基因组在发育中经受了修改,但这些修改并不是不可逆的。我们就此获得了对于细胞和有机体发育的一种新观点。
 
近年的研究显示,iPS细胞能够生成机体所有不同种类的细胞。这些发现也为全球科学家提供了新工具,使得他们在医学的许多领域做出了非凡的成就。iPS细胞也能从人体细胞中获得。
 
例如,可从罹患各种疾病的病人身上获得皮肤细胞,进行重编程,并在实验室进行检测以确定它们与健康人体细胞的不同。这些细胞对于理解疾病机制提供了无价的工具,从而为开发医学疗法提供了新机会。

山中伸弥(Yamanaka),是诱导多功能干细胞(iPScell)创始人之一。1962年出生于日本大阪府,日本医学家,京都大学再生医科研究所干细胞生物系教授,大阪市立大学医学博士(1993年),美国加利福尼亚州旧金山心血管疾病研究所高级研究员.2007年,他所在的研究团队通过对小鼠的实验,发现诱导人体表皮细胞使之具有胚胎干细胞活动特征的方法。此方法诱导出的干细胞可转变为心脏和神经细胞,为研究治疗目前多种心血管绝症提供了巨大助力。这一研究成果在全世界被广泛应用,因为其免除了使用人体胚胎提取干细胞的伦理道德制约。山中伸弥也因此获得2009年拉斯克基础医学奖。同时他在2008年获颁邵逸夫生命科学与医学奖。并于2011年获得国际最高学术大奖之一的沃尔夫医学奖,与其一起获奖的还有美国怀特黑德研究所的Rudolf Jaenisch。2012年,山中伸弥与美国软件工程师利努斯·托瓦兹获得芬兰“千年技术奖”,二人分别获得60万欧元的奖金。

约翰﹒戈登(John Gurdon),生于1933年10月2日,英国发育生物学家。他在细胞核移植方面进行了开创性的研究。2009年获得拉斯克基础医学奖。

据财经网报道,受经济危机影响,诺贝尔基金会宣布奖金将由以往1000万瑞士法郎缩水至800万瑞士法郎。

2011年10月3日,瑞典卡罗林斯卡医学院宣布,将2011年诺贝尔生理学或医学奖授予美国科学家布鲁斯·比特勒、法国科学家朱尔斯·霍夫曼和加拿大科学家拉尔夫·斯坦曼。1958年,他在牛津大学成功做出了体细胞克隆蛙。 

The Nobel Assembly at Karolinska Institutet has today decided to award

The Nobel Prize in Physiology or Medicine 2012

jointly to John B. Gurdon and Shinya Yamanaka

for the discovery that mature cells can be reprogrammed to become pluripotent

Summary

The Nobel Prize recognizes two scientists who discovered that mature, specialised cells can be reprogrammed to become immature cells capable of developing into all tissues of the body. Their findings have revolutionised our understanding of how cells and organisms develop.

John B. Gurdon discovered in 1962 that the specialisation of cells is reversible. In a classic experiment, he replaced the immature cell nucleus in an egg cell of a frog with the nucleus from a mature intestinal cell. This modified egg cell developed into a normal tadpole. The DNA of the mature cell still had all the information needed to develop all cells in the frog.

Shinya Yamanaka discovered more than 40 years later, in 2006, how intact mature cells in mice could be reprogrammed to become immature stem cells. Surprisingly, by introducing only a few genes, he could reprogram mature cells to become pluripotent stem cells, i.e. immature cells that are able to develop into all types of cells in the body.

These groundbreaking discoveries have completely changed our view of the development and cellular specialisation. We now understand that the mature cell does not have to be confined forever to its specialised state. Textbooks have been rewritten and new research fields have been established. By reprogramming human cells, scientists have created new opportunities to study diseases and develop methods for diagnosis and therapy.

 

Life – a journey towards increasing specialisation

All of us developed from fertilized egg cells. During the first days after conception, the embryo consists of immature cells, each of which is capable of developing into all the cell types that form the adult organism. Such cells are called pluripotent stem cells. With further development of the embryo, these cells give rise to nerve cells, muscle cells, liver cells and all other cell types - each of them specialised to carry out a specific task in the adult body. This journey from immature to specialised cell was previously considered to be unidirectional. It was thought that the cell changes in such a way during maturation that it would no longer be possible for it to return to an immature, pluripotent stage.

Frogs jump backwards in development

John B. Gurdon challenged the dogma that the specialised cell is irreversibly committed to its fate. He hypothesised that its genome might still contain all the information needed to drive its development into all the different cell types of an organism. In 1962, he tested this hypothesis by replacing the cell nucleus of a frog's egg cell with a nucleus from a mature, specialised cell derived from the intestine of a tadpole. The egg developed into a fully functional, cloned tadpole and subsequent repeats of the experiment yielded adult frogs. The nucleus of the mature cell had not lost its capacity to drive development to a fully functional organism.

Gurdon's landmark discovery was initially met with scepticism but became accepted when it had been confirmed by other scientists. It initiated intense research and the technique was further developed, leading eventually to the cloning of mammals. Gurdon's research taught us that the nucleus of a mature, specialized cell can be returned to an immature, pluripotent state. But his experiment involved the removal of cell nuclei with pipettes followed by their introduction into other cells. Would it ever be possible to turn an intact cell back into a pluripotent stem cell?

A roundtrip journey – mature cells return to a stem cell state

Shinya Yamanaka was able to answer this question in a scientific breakthrough more than 40 years after Gurdon′s discovery. His research concerned embryonal stem cells, i.e. pluripotent stem cells that are isolated from the embryo and cultured in the laboratory. Such stem cells were initially isolated from mice by Martin Evans (Nobel Prize 2007) and Yamanaka tried to find the genes that kept them immature. When several of these genes had been identified, he tested whether any of them could reprogram mature cells to become pluripotent stem cells.

Yamanaka and his co-workers introduced these genes, in different combinations, into mature cells from connective tissue, fibroblasts, and examined the results under the microscope. They finally found a combination that worked, and the recipe was surprisingly simple. By introducing four genes together, they could reprogram their fibroblasts into immature stem cells!

The resulting induced pluripotent stem cells (iPS cells) could develop into mature cell types such as fibroblasts, nerve cells and gut cells. The discovery that intact, mature cells could be reprogrammed into pluripotent stem cells was published in 2006 and was immediately considered a major breakthrough.

From surprising discovery to medical use

The discoveries of Gurdon and Yamanaka have shown that specialised cells can turn back the developmental clock under certain circumstances. Although their genome undergoes modifications during development, these modifications are not irreversible. We have obtained a new view of the development of cells and organisms.

Research during recent years has shown that iPS cells can give rise to all the different cell types of the body. These discoveries have also provided new tools for scientists around the world and led to remarkable progress in many areas of medicine. iPS cells can also be prepared from human cells.

For instance, skin cells can be obtained from patients with various diseases, reprogrammed, and examined in the laboratory to determine how they differ from cells of healthy individuals. Such cells constitute invaluable tools for understanding disease mechanisms and so provide new opportunities to develop medical therapies.

Sir John B. Gurdon was born in 1933 in Dippenhall, UK. He received his Doctorate from the University of Oxford in 1960 and was a postdoctoral fellow at California Institute of Technology. He joined Cambridge University, UK, in 1972 and has served as Professor of Cell Biology and Master of Magdalene College. Gurdon is currently at the Gurdon Institute in Cambridge.

Shinya Yamanaka was born in Osaka, Japan in 1962. He obtained his MD in 1987 at Kobe University and trained as an orthopaedic surgeon before switching to basic research. Yamanaka received his PhD at Osaka University in 1993, after which he worked at the Gladstone Institute in San Francisco and Nara Institute of Science and Technology in Japan. Yamanaka is currently Professor at Kyoto University and also affiliated with the Gladstone Institute.

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