生物谷報道：人類基因組計劃通過測序發(fā)現(xiàn)人類大約有3萬個基因，而大鼠,，小鼠等哺乳動物基因組也被測序完畢,，但是面對人們又產(chǎn)生了一個新的問題：如何研究這些基因的功能,？復旦大學發(fā)育生物學研究所即將發(fā)表在Cell上一篇文章揭開這一秘密,，該成果已由國際頂級生命科學雜志《細胞》在線發(fā)表(http://www.cell.com/content/future)，并將刊登在8月12日《細胞》雜志的封面,。
要解讀這本包羅生老病死等浩瀚奧秘的“天書”,，必須尋找到一種工具，能夠高效制造大面積基因突變和培育轉基因動物,。傳統(tǒng)的單個基因研究的方法極其緩慢,，已難以適應快速發(fā)展的基因組學的研究。如今,，這個“神奇工具”被中國科研人員發(fā)現(xiàn),。上海復旦大學發(fā)育生物學研究所的科研人員將一種源于飛蛾的PB(PiggyBac)轉座子（Transposon）用于小鼠和人類細胞的基因功能研究，在世界上首次創(chuàng)立了一個高效實用的哺乳動物轉座因子系統(tǒng),，為大規(guī)模研究哺乳動物基因功能提供了嶄新途徑,。
復旦大學于25日宣布：這一成果被國際一流的生命科學雜志《細胞》(CELL)作為封面文章發(fā)表，第一作者丁昇是復旦大學三年級研究生,。相關技術已申請國際專利,。這個源于飛蛾的PB轉座子被賦予了“夸蛾因子”的中國名字，“夸蛾”是古文《愚公移山》中的大力士,。
我們知道,，轉座子是一種可以進入基因組內(nèi)不同位置的基因載體?？茖W家利用它們插入基因導致突變以了解基因功能,，也利用它們培育轉基因生物。麥克林托克(B. McClintock)因首先在玉米中發(fā)現(xiàn)轉座因子而獲得了1983年諾貝爾醫(yī)學獎,。許田博士和吳曉暉博士共同領導的研究小組發(fā)產(chǎn)生了一個重要的idea：如果我們在轉座子中引入突變,，那么這個突變可以被轉座子帶到基因組的不同地方，從而引起大量的基因突變,，產(chǎn)生大量的表型,，由于突變的已知性,，從而可以利用這些突變直接找到與表型相對應的基因,。這是多么美妙的一個idea!由
然而，這有一個巨大障礙,，因為在哺乳類動物中幾乎找不到天然活性的轉座因子,！長期以來，為尋找一種對哺乳動物高效,、實用的轉座因子,，世界各國的科學家投入了大量的熱情和精力,。
復旦科學家們想到一個新的突破方案：與哺乳動物較接近的飛蛾，或果蠅類動物中,，轉座子是比較明朗,，那么能否進行移花接木？
在這一大膽的假設前提下,，他們利用飛蛾體內(nèi)一種常見的轉座子PB,，經(jīng)過改造后，作為重要的靶點,，將PB轉座因子高效插入小鼠基因組,，還可以培育轉基因小鼠。同時,，PB轉座因子可在人等哺乳動物的細胞株中高效導入基因并穩(wěn)定表達,，為體細胞遺傳學研究和基因表達提供了一個高效、便捷的新系統(tǒng),?！都毎冯s志審稿人評價：“這是里程碑式的發(fā)現(xiàn)，將可能在世界范圍內(nèi)改變小鼠遺傳學研究,，并有用于人類基因治療的前景 (these are landmark finding with the potential to alter the way mouse genetics is carried out worldwide, and with implications for human gene therapy. ）”,。
在過去的30多年中，全世界科學家凝聚大量的人力物力,，對約10%的哺乳動物基因的功能有所了解,，而復旦大學的研究小組用PB轉座因子建立了小鼠體內(nèi)直接突變基因技術，在不到一年內(nèi)培育出約1%小鼠基因的突變品系,，為大規(guī)模研究小鼠等哺乳動物基因功能提供了解決方案,。運用基因剔除方法，2位研究人員需要用上1年的時間才能分析2個基因的功能,；而復旦大學的2位研究人員僅僅用了3個月就研究了70多個基因,。
復旦發(fā)育生物學研究所由旅美華人學者許田韓珉和莊原共同創(chuàng)立，并得到了教育部,、國家自然科學基金和上海市科委的大力支持,，也得到美國休斯醫(yī)學研究院、耶魯大學,、科羅拉多大學和杜克大學的支持和合作,。研究所堅持以世界一流學術中心為標準，堅持源頭創(chuàng)新,，堅持在創(chuàng)新中培養(yǎng)高質(zhì)量的人才,。成立三年半來，全體人員臥薪嘗膽,，艱苦創(chuàng)業(yè),，已把研究所建成發(fā)育生物學學科建設和人才培養(yǎng)的基地,。論文第一作者丁昇是復旦三年級研究生。 運用PB轉座因子研究新方法可以在大范圍內(nèi)快速尋找疾病相關基因,，建立多種疾病模型,，尋找疾病機理和藥物靶點，從而發(fā)現(xiàn),、創(chuàng)新治療手段和藥物,，也為人類疾病的基因治療提供了新途徑。新方法還可以用于鑒定并研究具有重要生物學功能的基因,，并改良經(jīng)濟動物,。目前，以PB轉座因子技術體系為依托,，大規(guī)模研究基因功能的小鼠功能基因組計劃已經(jīng)在復旦大學啟動,。
生物谷專家認為，由于99%的人類基因在小鼠中有同源性,，因此,，小鼠是研究哺乳動物和人類基因功能的模式生物。這將對人類了解自身,、預防和治療各類疾病產(chǎn)生重要和深遠的影響,。這一工具將在高通量的功能基因組學研究中產(chǎn)生深遠的影響。這種可控的突變方法較傳統(tǒng)的ENU突變有明顯的可控性和優(yōu)勢,，具有極其廣闊和應用前景和價值,。
同時，生物谷專家也認為,，這篇文章的另一層意義也在于中國科學家在2005年,，科研水平有全面的突破和發(fā)展。僅僅2005年這半年多時間,，已有四篇Cell已發(fā)表,，這一成就是矚世舉目的！生物谷對每一篇文章的發(fā)表都做了大量篇幅報道,，使更多的讀者了解了國內(nèi)生物學的令人激動的快速發(fā)展歷程,。同時，據(jù)生物谷的信息,，中科院上海生命科學研究院有一篇Cell文章已投稿,，同時國內(nèi)還有一篇文章也正向Cell投稿，無論如何,，2005年都是中國生物學的豐收年和大突破年,，可能成為中國生物學的正在崛起的標志性一年,！
Sheng Ding, Xiaohui Wu, Gang Li, Min Han, Yuan Zhuang, and Tian Xu. Efficient Transposition of the piggyBac (PB) Transposon in Mammalian Cells and Mice. Cell. Published online Jul. 21, 2005
10.1016/S009286740500707 全文下載[PDF文件]
專題：
[專題]基因組和蛋白質(zhì)組學
復旦發(fā)育生物研究所介紹：
The Institute of Developmental Biology and Molecular Medicine (IDM) is an international biomedical research center. The IDM was funded by Fudan University and was further supported by the Science and Technology Commission of Shanghai Municipality and other funding agencies including the National Natural Science Foundation of China (NSFC). Its laboratory was first opened in Feb. 2002. The IDM pursues broad biomedical researches with a strong effort in the area of developmental biology and molecular mechanisms of human diseases. The IDM offers competitive training programs for highly motivated trainees at both graduate and post graduate levels. As an international academic research center, the IDM promotes scientific and educational exchanges with international scholars. The IDM works closely with the School of Life Science, Fudan University and the Morgan-Tan International Center for Life Sciences in building scientific and academic excellence in China.
DIRECTORS
Tian XU (許田), Ph.D.
-Guest Professor, FDU
-Professor and Vice Chairman, Genetics Department, Yale University
-HHMI Investigator
Min HAN (韓珉), Ph.D.
-Guest Professor, FDU
-Professor, Colorado University
-HHMI Investigator
Yuan ZHUANG (莊原), Ph.D.
-Guest Professor, FDU
-Associate Professor, Duke University
DEPUTY DIRECTOR
Beibei YING (應蓓蓓)
-Director of Graduate Study
-Senior Engineer, FDU
FACULTY MEMBERS
Kejing DENG (鄧可京), Ph.D.
-Associate Professor, FDU
Ling SUN (孫璘), Ph.D.
-Associate Professor, FDU
Wufan TAO (陶無凡) , Ph.D.
-Professor, FDU
Xiaohui WU (吳曉暉), Ph.D.
-Associate Professor, FDU
Rener XU (徐人爾), Ph.D.
-Associate Professor, FDU
Xiaodong WANG (王曉東), Ph.D.
-Adjunct Professor, FDU
-Professor, UTSW
-HHMI Investigator
-Member of National Academy of Sciences, USA
Yue XIONG (熊躍), Ph.D.
-Adjunct Professor, FDU
-Professor, University of North Carolina
實際日常在該所工作的有
許田,、韓珉,、莊原
應蓓蓓、鄧可京,、孫lin,、吳曉暉、徐人爾,、陶無凡
可以進行所有常規(guī)的小鼠,、果蠅、線蟲遺傳學實驗
分子生物學和細胞生物學實驗
經(jīng)費比較充足,、儀器比較充分,、鼓勵學生發(fā)揮自己的主觀能動性
HHMI成員許田，韓珉能提供全面指導,，但基本不包括親手示范實驗
Research Interests
The striking gene conservation between humans and model organisms such as mice, the fruit flies, Drosophila melanogaster, and the nemetode worms, C. elegans, provide a unique opportunity to study gene functions in model organisms. The ability to make crosses between genetically defined strains under controlled environment conditions, to work with large sample sizes, to generate transgenic and knockout animals with mutations in specific genes provide these animal models with powerful genetics. Combining the genetics with the enriched knowledge of the developmental biology in these model organisms, research in these animals has contributed and will still provide the majority of our current knowledge of gene functions and modern biology.
IDM uses multiple model organisms including mouse, fruit fly, and soil worm to study a number of important biological problems related to animal development and human diseases. We are particularly interested in the mechanisms of animal size control, tumorigenesis and metastasis, neural degeneration, and developmental pattern formation. We are also developing new genetic tools in mouse to facilitate functional genomic analysis.
Systematic Analysis of Human Gene Functions in Transgenic Animals
The human genome sequence has been determined. The current challenge is to understand the functions of the genes encoded by the human genome. One of the most powerful ways to reveal gene functions is genetically alternating genes in organisms and observing the phenotypic consequences. Genetic organisms such as mouse, Drosophila melanogaster, and C. elegans, are some of the most powerful models for large-scale genetic manipulations.
We are currently utilizing Drosophila and mouse to perform large-scale functional genomic studies in our institute. The first step of this research is to probe functions of human genes or their homologues by a systematic overexpression screen. The advantages of Drosophila genetics allow us to get the functional clues fairly efficiently. Following the leads from the screen results, genetic and biochemical analyses including generating transgenic, and in some cases gene knock-out mice are being or will be carried out to study the functions of the selected genesc. With this strategy, we have currently finished screening more than 300 human genes, and got dozens of positive results. Several animal models of common human diseases have also been developed.
Cell and Animal Size Regulation
Size is one of the most obvious characters of different species. Recently, many oncogenes and tumor suppressor genes have been found to be involved in cell or organism size control, suggesting that the size regulatory mechanisms also play critical roles in disease processes such as tumorigenesis that require increases in tissue size.
In Drosophila and in mammals, the Insulin/PTEN/TSC signaling pathway and the ras signaling pathway are two major players in cell size regulation. In mammals, these two pathways are known to be involved in various important developmental and disease processes, such as tumorigenesis. It is thus important to identify new factors that act in or with these pathways to regulate cell and animal sizes. Among many candidate genes we have identified through the overexpression screens, one was identified to be a component of the translation machinery. The characterizaition of this gene by a student indicate that it acts downstream of a known size control mechanism in Drosophila.
In addition, we have generated transgenic and knock-out mice for several components of the Insulin/PTEN/TSC as well as other evolutionarily conserved tumor suppressor genes such as lats. These mutants are now being studied to explore the relationship between size control mechanism and tumorigenesis in mammal.
Regulation of Ras Signaling Pathways
The Ras-mediated signaling pathways are involved in many critical cellular events including cell proliferation and differentiation. Multiple model organisms are being used to study certain regulatory aspects of this pathway. We have generated knockout mouse of the sur-8 gene that plays critical role in regulating the activation of Raf kinase by Ras. Preliminary results indicate that the gene is essential for mouse development. We are also cloning and characterizing a previously unknown gene that negatively regulates Ras/MAP kinase signaling activity in C. elegans. Biochemical and mouse genetics work will immediately follow once the worm gene is fully characterized. In addition, chemical genetic method will be explored to discover new means to suppress the activity of this signaling pathway.
Metastasis
Metastasis is the major cause of mortality for cancer patients. Given that the genetic alterations that cause metastasis are usually late events and that multiple genetic alterations occur in late stage cancers, traditional approaches have not been fruitful in identifying genes involved in metastasis. Professor Xu has designed a genetic screen in Drosophila to interrogate the genome for mutations that can cause otherwise noninvasive tumors of the eye disc to exhibit metastatic behaviors, such as the invasion of neighboring or distant tissues. We are systematically interrogating the Drosophila genome to identify genes and mechanisms that either promote or block metastatic behavior. Given that the genes we have identified are evolutionarily conserved, the results of such experiments will lend greater insights into the genetic mechanisms that regulate metastasis in humans. Once the genes are identified through genetic work in Drosophila, characterization of them using mouse genetics will immediately follow.
Neurodegeneration & Transcription Regulation
The expansion of polyglutamine tracks has been identified as the cause for a growing number of progressive neurodegenerative diseases including Huntington\'s disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA). However, the in vivo functions of Atrophin-1 and Huntingtin, as well as the mechanism of neurodegeneration caused by polyglutamine expansion, is unknown. It has been illustrated by Professor Xu and his students that the Drosophila and human Atrophin homolog functions to repress transcription in Drosophila embryos. To test whether deregulation of transcription dose contribute to the pathogenesis of neurodegeneration in mammal, we have created a transgenic mouse model for DRPLA. Severe neurodegenerative phenotypes develop progressively after the animal reaches its adulthood. Interestingly, this process can be partially suppressed by a compound that involves in transcription regulation. The model could not only help to learn more the role of transcription regulation in neurodegeneration, but also serve as a tool for the development of effective therapies against DRPLA and related diseases.
Mechanisms of Autoimmune Diseases
Lymphocyte development is controlled by a complex array of regulatory molecules including extra-cellular signaling molecules, cell surface receptors, signal transducing kinases, and nuclear transcription factors. Abnormalities in lymphocyte development due to environmental insults or genetic alterations often lead to immune system diseases such as immune deficiency, autoimmune syndromes, or leukemia. We are using the concepts of molecular biology and mouse genetics to investigate the molecular mechanisms lymphocyte development. Professor Zhuang and his student of our institute have recently established a mouse model of Sjögren syndrome, the second most common autoimmune rheumatic disease [Immunity, in press]. This work provides a novel animal model of studying pathogenesis of the disease, the generation of autoimmune cells, and most importantly clues for further clinical prevention, diagnosis and therapy.
Mouse Balancer Chromosome
Although mice share great similarity with human, many useful genetic methods are currently unavailable in mice. One of these is the use of balancer chromosomes. A Balancer chromosome is a particularly useful chromosomal rearrangement that carries multiple inversions, which can effectively suppress homologous recombination within the inverted regions. Originally used in Drosophila melanogaster, balancer chromosomes greatly facilitated the maintenance of recessive lethal mutations, which could play a critical role in large-scale mutagenesis screens in mice. We are currently generating balancer chromosomes of mouse chromosomes 13 and 17. These strains will be extremely helpful for mutagenesis screens that focus on functional annotation of the genes in these two regions, such as the MHC cluster genes on chromosome 17.
Functional Genomics of Model Organisms
Genomics tool has become well established in current biological studies. The sequencing of whole genome has formed the basis for the study of the activity of the whole genome, which is the components of life. Not only when we fully understand how each molecule of life works, but also how they cooperate together, would we be able to know the how life came into being.
This aspect of research at IDM wants to use functional genomics tools (microarray, tissue array, section array, and bioinformatics) combined with other molecular biology tools such as RNAi, etc. to help addressing the questions related to model organism development and mechanism of human diseases.
學生對發(fā)育生物研究所的評價：
來源：http://www.bioon.net/dispbbs.asp?boardid=115&id=134852
評價1：首先不得不承認,，發(fā)育基地真的是一個很鍛煉人的地方。別的實驗室一般總會有幾個師
哥師姐帶帶什么的,，在基地里,，你做得就是自己的課題，小到設計一條引物,，大到整個實驗的設計,，方向，基本都要靠自己把握,，當然老師會在邊上給予一定的幫助,。
其次，發(fā)育基地的研究學習氛圍很好,，每周六是labmeeting,，大家自己介紹自己的工作進展，大家討論討論,，一般都是比較激烈的,。周二是jourmal club，大家輪著介紹CELL paper（汗,，我明天就要第一次jourmal club,，還在準備），當然會議都是要求用e文來進行的,。平時家的工作時間是9：00－－21：00,，但是很少看見有同學會這麼準時下班的，不是老板push,，我覺得有時候完全是自己在push自己,。基地的同學都差不多,。
還有一點,，我要贊一下基地的設備,，我聽從yale回來的xx（不記得了，是老板,，是同學）說的,，這里怎么和yale的一模一樣。嘿嘿..... 我的感覺是,，為什么連tip都要進口,。
最后隨便說一下自己的工作吧，最近在做一個有關nuclear anchoring的protein,，用drosophila embryo system 來做,，作了幾個部分的實驗，RNAi,，germline mosaic,。
評價2：In IDM, students do not have an appointed teacher when they first arrived. Instead, they need to have rotation first. During rotation, new students will do
labwork under the direction of different teachers one after the other. It is t
he rotation that make new students be familiar with different teachers. And it is the rotation that provide oppotunities for teachers to know students better.
After students finish rotation, they will have one teacher as their "primary"
mentor. This appointment is based on a mutual selection mechanism. However, a
t the same time, all other teachers have nearly the same responsibility as the
"primary" mentor. In other words, students have shared mentors in IDM, while teachers have shared students as well. This unique feature makes IDM more like a super lab and make s it unnecessary to write to individual teacher for a better chance to be recruited.
