瑞典皇家科学院7日宣布，将2009年诺贝尔化学奖授予美国科学家文卡特拉曼·拉马克里希南、托马斯·施泰茨和以色列女科学家阿达·约纳特，以表彰他们在核糖体结构和功能方面取得杰出的研究成果。

　　瑞典皇家科学院诺贝尔奖委员会当日表示，三人获奖的理由是他们的研究成果揭示了核糖体的结构和运行方式，而这对研发新型抗菌素有重要意义。

　　了解核糖体内在工作的机理，对于科学理解生命非常重要。核糖体相当于细胞的蛋白质工厂里的工程师，它的工作是将细胞里ＤＮＡ分子所含有的各种遗传密码翻译出来，以生成各式各样的蛋白质。人体内有成千上万种蛋白质，它们各自拥有不同的形式与功能，在化学层面上构建并控制着生命体。不难理解，如果细菌的核糖体功能得到抑制，那么细菌就无法存活。在医学上，人们正是利用抗生素来抑制细菌的核糖体从而治疗疾病的。

　　诺贝尔奖评委会介绍，三位科学家都采用了Ｘ射线蛋白质晶体学的技术，标识出了构成核糖体的成千上万个原子。这些科学家们不仅让我们知晓了核糖体的“外貌”，而且在原子层面上揭示了核糖体功能的机理。他们设计的三维计算机模型可以显示不同的抗生素是如何抑制核糖体功能的，这种模型已经被用于研发新的抗生素。

　　文卡特拉曼·拉马克里希南1952年出生于印度，先后在印度、美国多所大学求学，并曾在美国耶鲁大学等高校工作，1999年进入英国剑桥大学ＭＲＣ分子生物学实验室工作，持有美国国籍。过去，他就曾因在组蛋白和染色质方面的研究备受关注。关于核糖体研究，他的贡献是设计出了核糖体亚单位的三维模拟结构。

　　美国科学家托马斯·施泰茨现年69岁，出生于美国威斯康星州，现在是美国耶鲁大学教授，他同时也在霍华德·休斯医学院工作。施泰茨在1966年获得美国哈佛大学博士学位，也曾经在英国剑桥的分子生物实验室工作过。他的主要贡献也是揭示了核糖体的结构和运行方式以及抗生素与核糖体结合的机制。

　　现年70岁的以色列女科学家阿达·约纳特1939年出生在耶路撒冷一个贫困的犹太家庭，父母没有受过良好的教育，但却非常支持女儿的学业。约纳特在耶路撒冷希伯莱大学获得本科和硕士学位，在以色列魏兹曼科学院拿到了博士学位，现在仍在魏兹曼科学院工作。1970年，她创立了以色列第一家蛋白质结晶实验室。多年来，她的研究方向一直是通过核糖体结晶学来研究蛋白质的生物合成。　

　　阿达·约纳特在第一时间接到了获奖通知，她表示，自己刚刚从惊喜中恢复了过来，获奖消息对她来说简直是喜从天降，让她非常高兴。她说，自己在开始研究这项课题的时候，就知道自己从事的是其一生中最重要的课题。　

　　据悉，三位化学家将分享1000万瑞典克朗，约合140万美元的奖金。

Jack W. Szostak

The key concepts of genetics are phenotype and genotype: genotype is generally embodied in a nucleic acid sequence, and phenotype represents some observable property of an organism. Moving these ideas from the organismal to the molecular level leads naturally to the idea of creating and manipulating genetic variation in molecules, entirely in vitro. The discovery of catalytic RNAs in the early 1980s demonstrated that RNA could manifest a range of interesting phenotypes. Simultaneously, the invention of the polymerase chain reaction made it easy to replicate almost any nucleic acid sequence in vitro. Together these advances inspired the development of practical ways of using in vitro selection and directed evolution to search sequence space, the ensemble of all possible sequences, for new functional RNA, DNA, and protein sequences.
The simplest interesting phenotypes of RNAs and DNAs are binding properties. In vitro selection for sequences that fold up into specific three-dimensional structures that contain highly specific binding sites has been used to isolate many nucleic acids, called aptamers, that bind a wide range of small biomolecules, including nucleotides, amino acids, antibiotics, and cofactors. We have found that these nuceic acid molecules can be selected successfully for catalysis as well.

Application of the principles of in vitro selection and directed evolution to peptides and proteins is a powerful tool for investigating protein function and structure and for obtaining insight into the pathways by which enzymes evolve in nature. Our approach has been to generate stable, covalent RNA-protein fusions in a completely in vitro system. We do this by covalently linking puromycin, an antibiotic that mimics an aminoacylated tRNA, to the 3\' end of a synthetic mRNA through a DNA linker. A ribosome begins translation of such a template as usual, generating a peptide as it transits the open reading frame. When the ribosome reaches the end of the open reading frame and hits the DNA linker it stalls, allowing the nearby puromycin to enter the A site of the ribosome and accept the nascent peptide chain. The resulting RNA-peptide fusions can be formed efficiently from mRNAs encoding small peptides or large proteins. We have prepared libraries of fusions encoding random peptides and are preparing to begin evolving new binding domains and enzymes. An exciting future application will be the ability to conduct side-by-side comparisons of RNA and protein evolution. (This work was supported in part by grants from the National Institutes of Health.)

First Glimpse of Telomerase

Throughout the late 1970s and early 1980s, Blackburn and other researchers had found that telomeres show unusual behavior and structure. The chromosome caps consist of multiple repeats of a simple motif, which in the pond ciliate Tetrahymena was six nucleotides long. The mechanism by which these sequence repeats were added to the ends of telomeres in ciliates and yeast had not yet been identified. Most researchers believed recombination was responsible, but Blackburn favored the explanation of specific repeat addition by an as-yet-unknown enzyme. She decided that Tetrahymena, a pond ciliate with a macronucleus and 40,000 telomeres, was a natural place to look. When she started work in Black-burn\'s laboratory in April 1984, Greider set out to find this hypothetical enzyme in Tetrahymena.

It was a tall order for a graduate student, but Greider was clearly up to the task, says Blackburn, now the Morris Herzstein Professor of Biology and Physiology in the Department of Biochemistry and Biophysics at the University of California, San Francisco. “If you were easily intimidated, you wouldn\'t take on that kind of project,” Blackburn says. “We had to be both rigorous and enterprising, and those are exactly the characteristics that Carol has. The combination is a great strength.” For her part, Greider worked 12-hour days and supplemented her existing biochemistry knowledge with DNA cloning techniques and other skills needed for the project.

Nine months after she began the project, and after much trial and error finding the right substrate and assay, Greider identified the first signs of her enzyme. On Christmas Day in 1984, she developed one of her gels and saw a ladder of the characteristic Tetrahymena 6-base telomeric repeats—exactly the pattern that would be expected from a telomere-synthesizing enzyme. But she and Blackburn did not celebrate right away. Greider says, “When you find something that is really exciting that you think may be something new, the first things that go through your mind should be, `What else could it be? How could I be being fooled?”\'

Many potential sources of artifacts existed, and Greider and Blackburn wanted to rule out as many as possible. In June 1985 came the persuasive experiment, which showed that yeast telomeres functioned in Tetrahymena and indicated that they were seeing a new enzyme activity. This time, Greider went home and celebrated. Publishing in December 1985, Greider and Blackburn originally called the newly discovered activity “Tetrahymena telomere terminal transferase” because it seemed to add telomere repeats in a manner similar to terminal transferase (2). Deciding that this name was “a mouthful,” Greider says, they later shortened it to “telomerase.”

Previous SectionNext SectionFreedom in the Academic Laboratory
For the next two and a half years, Greider purified and further characterized telomerase. In the laboratory, she and Blackburn enjoyed hashing out the problems, Greider says, and they would often end up arguing opposite sides of a debate until each had convinced the other of her side. “Carol is a marvelous person to discuss science with,” Blackburn says. “She\'s very lively and interactive.”

On the advice of her thesis committee, Greider sought a postdoctoral fellowship at Cold Spring Harbor Laboratory in Long Island, NY, in 1987. The laboratory gave her the option to bypass the usual process of working in one researcher\'s laboratory and instead to work completely independently in her own laboratory as a Cold Spring Harbor Fellow. “That was a really good position for Carol, given her interest and her high abilities,” Blackburn says. When she moved to Cold Spring Harbor, Greider continued work to clone the gene that encoded the RNA component of telomerase. She published the results of this work in 1989 (3).

Greider soon found a graduate student who wanted to work in her laboratory, and she tried to squeeze the student into her limited funding. Cold Spring Harbor then told Greider that if she could obtain a grant from the National Institutes of Health (NIH; Bethesda, MD), she could have a graduate student as well as be a full staff member. Funds were tight, Greider says, but she managed to obtain the NIH funding. Lea Harrington joined Greider\'s laboratory as her first graduate student, and in 1990 Greider was promoted to Assistant Investigator.

During this time, Greider began work with Calvin Harley at McMaster University (Hamilton, Ontario, Canada). The collaboration combined Harley\'s interest in cellular senescence and Greider\'s interest in telomeres. Together, in 1990, they provided early evidence that telomere length was related to cellular aging (4). Greider\'s laboratory also collaborated with Harley\'s to investigate telomere shortening in cancer cells. They found that the gene for telomerase is activated in cancer cells, which allows these cells to bypass cellular senescence and continue growing as immortalized cells (5). Both of these results posed great implications for understanding aging and treating cancer.

“We wanted to ask genetic questions about what happens to cells when they lose telomerase.”

Greider first concentrated her efforts on cancer because the relationship between telomeres and cancer cells made telomerase a potential target for cancer chemotherapy. “Being a molecular biology and genetics lab, we wanted to ask genetic questions about what happens to cells when they lose telomerase,” Greider says. Instead of inhibiting the enzyme, Greider and her group developed a mouse model and knocked out the gene for telomerase to mimic a telomerase inhibitor. “That\'s when we set out to clone the mouse and human RNA component, so that we could do those kinds of studies,” she says.

When Harley moved his laboratory from McMaster University to be part of Geron, a new biotechnology company in Menlo Park, CA, their relationship began to change. At first, Greider continued her collaboration with Harley and was a founding member of the advisory board for Geron. Together, their laboratories cloned the gene for human telomerase RNA, and, later, Greider\'s laboratory cloned the mouse gene (6, 7). Yet Greider began to see the business and academic research paradigms clash. Geron, like most biotechnology companies, had an active public relations division. Small biotech companies particularly need to have their names publicized, Greider says, and Geron was successful at this. “But that really conflicts with what I saw as a very straightforward, honest science principle: Don\'t overstate things,” she says. Just as Greider was cautious not to prematurely celebrate her original Tetrahymena telomerase finding, she also wanted to take this careful approach with advances at Geron. “The rhetoric in an academic area and in a business are very different. So I went off the advisory board.”

Previous SectionNext SectionJuggling Students and Post-Docs
Over time, Greider became increasingly interested in the physiological effects of telomerase in mammals and how the biochemistry of mammalian telomerase differs from that of microorganisms. Her laboratory created a knockout mouse allowing them to address such questions . “I decided to focus on the mouse and separate myself from [Geron] to some degree, so I could do the kinds of really academic studies I wanted to do,” she says.

In 1997, Greider and her husband, Nathaniel, a science historian, moved to Maryland to take on positions at neighboring universities. Her husband worked at The George Washington University in Washington, DC, while Greider accepted an associate professor position at The Johns Hopkins University School of Medicine in Baltimore, MD. It was a good move, she says, because she wanted to work with more graduate students. Cold Spring Harbor is “post-doc heavy,” she explains. “With all post-docs, there\'s a lot of pressure in terms of them getting a job and having their own territory. Graduate students are a little more open to trying different things. There\'s a different speed at which they learn.” Students now fill more than half her laboratory at Johns Hopkins. “I select for people that like to be very independent,” she says. “It\'s more like having a day-to-day collaboration with smart people, and I find that fun.”

One group within Greider\'s laboratory has continued her original biochemistry research, working to establish the structural and functional regions within the telomerase RNA (9, 10). Another group is exploring genetic questions with yeast. “It turns out that the biology of something as fundamental as telomeres is so conserved in a variety of organisms, that what you find out in yeast also turns out to be true in mammalian cells,” Greider explains. Her laboratory has performed experiments studying the role of telomeres in genomic stability, DNA damage, and cell death (11–13).

In her Inaugural Article, Greider and former postdoctoral student Jiunn-Liang Chen explore the structure of the RNA subunit of human telomerase (1). “My roots are in the biochemistry of telomerase,” she says. “Since I started in that area, I\'ve spread out into more cell and organismal biology, cancer, and aging. I thought it appropriate that the Inaugural Article goes back to the biochemistry that was the heart of how I started.” Their work looks specifically at the pseudoknot structure of the RNA component, which has been conserved in all vertebrates and is essential for telomerase activity. Some researchers have proposed that the pseudoknot essentially switches between two different conformations. In their article, Greider and Chen give strong evidence against this idea, and their results support a static pseudoknot structure.

Previous SectionNext SectionNew Links to Old Interests
Greider\'s latest line of research takes advantage of these structural studies for a clinical application to dyskeratosis congenita, a rare, inherited disorder related to stem cell failure. Recently, various forms of the disease have been linked to mutations in proteins that bind to telomerase RNA or in telomerase RNA itself. Persons with dyskeratosis congenita cannot maintain the telomerase in their bone marrow and eventually die of bone marrow failure. “Suddenly, the studies that we had done, very careful studies on the structural function of the RNA, were pertinent to this disease,” Greider says. “It\'s another example of curiosity-driven research ending up having a direct medical implication.”

Greider is intrigued to find stem cells linked with telomeres and is currently developing mouse models to understand how telomerase may play a role in stem cell failure. This might lead to a clearer link between organismal aging and telomeres, she says. “I\'m not a believer that aging is going to be one thing, that there\'s going to be one gene that controls all of aging. I think there are going to be multiple different failures, and that the loss of stem cells can play a role in a number of them.”

This area is also a chance to explore another line of research, something Greider always enjoys. “It\'s completely new, and I\'m intrigued by new things. Any time you do a series of experiments, there are going to be three or four new questions that come up when you think you\'ve answered one.” She plans to keep following her research instincts wherever they take her. “You might as well set up your lab and the kinds of experiments you do to give yourself the most freedom,” she says. “It\'s going to be hard work whether you think it\'s fun or not, so you might as well have fun while you\'re doing the hard work.”

颁奖理由

中国网10月5日报道 据美联社报道，瑞典卡罗林斯卡医学院今天宣布，将2009年诺贝尔生理学或医学奖授予美国加利福尼亚旧金山大学的伊丽莎白-布莱克本、美国巴尔的摩约翰-霍普金斯医学院的卡罗尔-格雷德、美国哈佛医学院的杰克-绍斯塔克。颁奖词称，这三人之所以获得诺贝尔奖，是因为他们的研究对癌症和衰老研究具有重要的意义。以下是颁奖词节选。

“今年的诺贝尔生理学或医学奖颁给三名科学家，他们解决了生物学的一个重大问题：在细胞分裂时染色体如何完整地自我复制以及染色体如何受到保护以免于退化。这三位诺贝尔奖获得者已经向我们展示，解决办法存在于染色体末端—端粒，以及形成端粒的酶—端粒酶。”

“携带基因信息的DNA线状长分子挤压形成染色体，端粒就像一顶高帽子置于染色体头上。伊丽莎白-布莱克本和杰克-绍斯塔克发现端粒的一种独特DNA序列能保护染色体免于退化。卡罗尔-格雷德和伊丽莎白-布莱克本确定了端粒酶，端粒酶是形成端粒DNA的成分。这些发现解释了染色体的末端是如何受到端粒的保护的，而且端粒是由端粒酶形成的。”

“如果端粒缩短了，细胞就会老化。相反，如果端粒酶的活动显著，端粒的长度也就能得以保持，并且细胞衰老也将延后。癌细胞就是一个例子，癌细胞被认为是具有永久生命力的。相反，某些特定的遗传疾病，会出现一些有缺陷的端粒酶这样的特征，导致损害细胞。对此诺贝尔奖颁给这一细胞基本机制的发现，这一发现有助于新的治疗措施的发展。”

总之，伊丽莎白-布莱克本、卡罗尔-格雷德以及杰克-绍斯塔克的发现提高了人们对于细胞的理解的深度，阐明了疾病机制，有助于未来新治疗方法的发展.

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