Biography of Carol W. Greider BIOGRAPHY

hen biochemist and mol- in Berkeley, things clicked again. ‘‘I re- ecular biologist Carol ally liked my conversations with Liz, and Greider was a first-year there were a number of other people in graduate student at the the department that would be poten- UniversityW of California, Berkeley, in tially fun to work with, so I went there,’’ 1984, she began to study a topic slightly says Greider. off the beaten path. With her adviser, Elizabeth Blackburn, Greider investi- First Glimpse of Telomerase gated how a certain single-celled pond Throughout the late 1970s and early organism maintained the tens of thou- 1980s, Blackburn and other researchers sands of caps on the ends of its mini- had found that telomeres show unusual chromosomes—specialized structures behavior and structure. The chromosome known as telomeres that protect against caps consist of multiple repeats of a sim- DNA damage. On Christmas Day, 9 ple motif, which in the pond ciliate Tetra- months later, Greider spotted signs of a hymena was six nucleotides long. The new enzyme, telomerase, that appeared mechanism by which these sequence re- to be responsible for this chromosomal peats were added to the ends of telomeres maintenance. The finding helped kick in ciliates and yeast had not yet been off a field of research that would attract identified. Most researchers believed re- the attention of longevity researchers, combination was responsible, but Black- cancer biologists, and the biotechnology burn favored the explanation of specific industry. repeat addition by an as-yet-unknown Today, so many papers are published enzyme. She decided that Tetrahymena, with the keyword ‘‘telomerase’’ in the Carol W. Greider a pond ciliate with a macronucleus and title—about 1,000 each year, at last 40,000 telomeres, was a natural place to count—that Greider cannot keep up look. When she started work in Black- with them all. Still, she delights in how would suit her as much as textbook learning did. Greider sampled a few lab- burn’s laboratory in April 1984, Greider the field’s research questions multiply set out to find this hypothetical enzyme in and expand with each new finding. ‘‘I oratories as a freshman, but, when she landed in a biochemistry laboratory the Tetrahymena. see telomeres as having taken me for a It was a tall order for a graduate stu- ride,’’ says Greider, who was elected to next year, she knew she had found her home. ‘‘You can’t really know without dent, but Greider was clearly up to the the National Academy of Sciences in task, says Blackburn, now the Morris 2003. Her work began in biochemistry being in a lab the style of science that it does,’’ she says. ‘‘But once you get into Herzstein Professor of Biology and but has changed over the years to inter- Physiology in the Department of Bio- sect with the fields of cellular senes- an environment that fits your own scien- tific way of thinking about problems, it chemistry and Biophysics at the Univer- cence, cancer, DNA recombination, and sity of California, San Francisco. ‘‘If you stem cell failure. In her Inaugural Arti- just clicks.’’ Greider stayed in the biochemistry were easily intimidated, you wouldn’t cle (1), published in this issue of PNAS, take on that kind of project,’’ Blackburn Greider explores the structure of the laboratory for two and a half years, en- joying lively conversations with other says. ‘‘We had to be both rigorous and RNA subunit of telomerase. ‘‘It’s fun, enterprising, and those are exactly the because I picked one topic, but the laboratory members and the mechanistic flavor of thinking that pervaded. Even characteristics that Carol has. The com- fields keep changing, so I have to keep bination is a great strength.’’ For her learning along the way,’’ she says. during her junior year abroad in Ger- many, she found a biochemistry labora- part, Greider worked 12-hour days and Clicking with Biochemistry tory in which to work. After this preview supplemented her existing biochemistry of graduate student life and research knowledge with DNA cloning tech- Greider grew up in Davis, CA, near the niques and other skills needed for the University of California, Davis campus, publishing responsibilities, the career BIOCHEMISTRY path of an academic scientist still ap- project. where her father was a physics profes- Nine months after she began the sor. While her high school classmates pealed to her. Greider applied to molec- project, and after much trial and error descended on the University of Califor- ular biology graduate programs across finding the right substrate and assay, nia, Davis, or nearby Berkeley for col- California. Greider identified the first signs of her lege, she decided to move down the Her application package was a bit enzyme. On Christmas Day in 1984, she coast to attend the University of Cali- unusual, Greider says. ‘‘I had great re- developed one of her gels and saw a fornia, Santa Barbara. ‘‘I didn’t want to search experience, great letters of rec- ladder of the characteristic Tetrahymena do what everyone else was doing,’’ she ommendation, and outstanding grades, 6-base telomeric repeats—exactly the says. Originally interested in marine bi- but I had poor GREs.’’ Although she pattern that would be expected from a ology, she enrolled in the university’s did not know it growing up, Greider telomere-synthesizing enzyme. But she College of Creative Studies, whose small suffers from dyslexia, which affected her and Blackburn did not celebrate right size meant its students could enjoy a scores on standardized tests. Only two high faculty-to-student ratio. schools—the California Institute of

Greider’s mentor, a dynamic re- Technology (Pasadena, CA) and the This is a Biography of a recently elected member of the searcher named Bea Sweeney, insisted University of California, Berkeley— National Academy of Sciences to accompany the member’s that she try out research right away, to offered her an interview. When she met Inaugural Article on page 8080. find out whether hands-on science with cell biologist Elizabeth Blackburn © 2005 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0503019102 PNAS ͉ June 7, 2005 ͉ vol. 102 ͉ no. 23 ͉ 8077–8079 Downloaded by guest on September 28, 2021 away. Greider says, ‘‘When you find During this time, Greider began work things,’’ she says. Just as Greider was something that is really exciting that you with Calvin Harley at McMaster Univer- cautious not to prematurely celebrate think may be something new, the first sity (Hamilton, Ontario, Canada). The her original Tetrahymena telomerase things that go through your mind should collaboration combined Harley’s interest finding, she also wanted to take this be, ‘What else could it be? How could I in cellular senescence and Greider’s in- careful approach with advances at be being fooled?’’’ terest in telomeres. Together, in 1990, Geron. ‘‘The rhetoric in an academic Many potential sources of artifacts ex- they provided early evidence that telo- area and in a business are very differ- isted, and Greider and Blackburn wanted mere length was related to cellular aging ent. So I went off the advisory board.’’ to rule out as many as possible. In June (4). Greider’s laboratory also collabo- 1985 came the persuasive experiment, rated with Harley’s to investigate telo- Juggling Students and Post-Docs which showed that yeast telomeres func- mere shortening in cancer cells. They Over time, Greider became increasingly tioned in Tetrahymena and indicated that found that the gene for telomerase is interested in the physiological effects of they were seeing a new enzyme activity. activated in cancer cells, which allows telomerase in mammals and how the This time, Greider went home and cele- these cells to bypass cellular senescence biochemistry of mammalian telomerase brated. Publishing in December 1985, and continue growing as immortalized differs from that of microorganisms. Greider and Blackburn originally called cells (5). Both of these results posed Her laboratory created a knockout the newly discovered activity ‘‘Tetrahy- great implications for understanding mouse allowing them to address such mena telomere terminal transferase’’ be- aging and treating cancer. questions (8). ‘‘I decided to focus on the cause it seemed to add telomere repeats mouse and separate myself from in a manner similar to terminal trans- [Geron] to some degree, so I could do ferase (2). Deciding that this name was ‘‘a ‘‘We wanted to the kinds of really academic studies I mouthful,’’ Greider says, they later short- wanted to do,’’ she says. ened it to ‘‘telomerase.’’ ask genetic questions In 1997, Greider and her husband, Nathaniel, a science historian, moved to Freedom in the Academic Laboratory about what happens Maryland to take on positions at neigh- For the next two and a half years, Greider boring universities. Her husband worked purified and further characterized telom- to cells when they at The George Washington University in Washington, DC, while Greider erase. In the laboratory, she and Black- lose telomerase.’’ burn enjoyed hashing out the problems, accepted an associate professor position Greider says, and they would often end at The Johns Hopkins University School of Medicine in Baltimore, MD. It was a up arguing opposite sides of a debate until Greider first concentrated her efforts good move, she says, because she each had convinced the other of her side. on cancer because the relationship be- wanted to work with more graduate stu- ‘‘Carol is a marvelous person to discuss tween telomeres and cancer cells made dents. Cold Spring Harbor is ‘‘post-doc science with,’’ Blackburn says. ‘‘She’s very telomerase a potential target for cancer heavy,’’ she explains. ‘‘With all post- lively and interactive.’’ chemotherapy. ‘‘Being a molecular biol- docs, there’s a lot of pressure in terms On the advice of her thesis committee, ogy and genetics lab, we wanted to ask of them getting a job and having their Greider sought a postdoctoral fellowship genetic questions about what happens to own territory. Graduate students are a at Cold Spring Harbor Laboratory in cells when they lose telomerase,’’ Gre- little more open to trying different Long Island, NY, in 1987. The labora- ider says. Instead of inhibiting the en- things. There’s a different speed at tory gave her the option to bypass the zyme, Greider and her group developed which they learn.’’ Students now fill usual process of working in one re- a mouse model and knocked out the more than half her laboratory at Johns searcher’s laboratory and instead to gene for telomerase to mimic a telomer- Hopkins. ‘‘I select for people that like work completely independently in her ase inhibitor. ‘‘That’s when we set out to to be very independent,’’ she says. ‘‘It’s own laboratory as a Cold Spring Harbor clone the mouse and human RNA com- more like having a day-to-day collabora- Fellow. ‘‘That was a really good position ponent, so that we could do those kinds tion with smart people, and I find that for Carol, given her interest and her of studies,’’ she says. fun.’’ high abilities,’’ Blackburn says. When When Harley moved his laboratory One group within Greider’s labora- she moved to Cold Spring Harbor, Gre- from McMaster University to be part of tory has continued her original bio- ider continued work to clone the gene Geron, a new biotechnology company chemistry research, working to establish that encoded the RNA component of in Menlo Park, CA, their relationship the structural and functional regions telomerase. She published the results of began to change. At first, Greider con- within the telomerase RNA (9, 10). this work in 1989 (3). tinued her collaboration with Harley Another group is exploring genetic Greider soon found a graduate stu- and was a founding member of the advi- questions with yeast. ‘‘It turns out that dent who wanted to work in her labora- sory board for Geron. Together, their the biology of something as fundamental tory, and she tried to squeeze the student laboratories cloned the gene for human as telomeres is so conserved in a variety into her limited funding. Cold Spring telomerase RNA, and, later, Greider’s of organisms, that what you find out in Harbor then told Greider that if she laboratory cloned the mouse gene (6, 7). yeast also turns out to be true in mam- could obtain a grant from the National Yet Greider began to see the business malian cells,’’ Greider explains. Her Institutes of Health (NIH; Bethesda, and academic research paradigms clash. laboratory has performed experiments MD), she could have a graduate student Geron, like most biotechnology compa- studying the role of telomeres in as well as be a full staff member. Funds nies, had an active public relations divi- genomic stability, DNA damage, and were tight, Greider says, but she man- sion. Small biotech companies particularly cell death (11–13). aged to obtain the NIH funding. Lea need to have their names publicized, In her Inaugural Article, Greider and Harrington joined Greider’s laboratory Greider says, and Geron was successful former postdoctoral student Jiunn-Liang as her first graduate student, and in at this. ‘‘But that really conflicts with Chen explore the structure of the RNA 1990 Greider was promoted to Assistant what I saw as a very straightforward, subunit of human telomerase (1). ‘‘My Investigator. honest science principle: Don’t overstate roots are in the biochemistry of telomer-

8078 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0503019102 Nuzzo Downloaded by guest on September 28, 2021 ase,’’ she says. ‘‘Since I started in that congenita, a rare, inherited disorder re- aging is going to be one thing, that BIOGRAPHY area, I’ve spread out into more cell and lated to stem cell failure. Recently, vari- there’s going to be one gene that con- organismal biology, cancer, and aging. I ous forms of the disease have been trols all of aging. I think there are going thought it appropriate that the Inaugu- linked to mutations in proteins that bind to be multiple different failures, and ral Article goes back to the biochemistry to telomerase RNA or in telomerase that the loss of stem cells can play a that was the heart of how I started.’’ RNA itself. Persons with dyskeratosis role in a number of them.’’ This area is also a chance to explore Their work looks specifically at the congenita cannot maintain the telomer- another line of research, something Gre- pseudoknot structure of the RNA com- ase in their bone marrow and eventually ider always enjoys. ‘‘It’s completely new, ponent, which has been conserved in all die of bone marrow failure. ‘‘Suddenly, and I’m intrigued by new things. Any time vertebrates and is essential for telomer- the studies that we had done, very care- you do a series of experiments, there are ase activity. Some researchers have pro- ful studies on the structural function of going to be three or four new questions posed that the pseudoknot essentially the RNA, were pertinent to this dis- that come up when you think you’ve an- switches between two different confor- ease,’’ Greider says. ‘‘It’s another exam- swered one.’’ She plans to keep following mations. In their article, Greider and ple of curiosity-driven research ending her research instincts wherever they take Chen give strong evidence against this up having a direct medical implication.’’ her. ‘‘You might as well set up your lab idea, and their results support a static Greider is intrigued to find stem cells and the kinds of experiments you do to pseudoknot structure. linked with telomeres and is currently give yourself the most freedom,’’ she says. developing mouse models to understand ‘‘It’s going to be hard work whether you think it’s fun or not, so you might as well New Links to Old Interests how telomerase may play a role in stem have fun while you’re doing the hard Greider’s latest line of research takes cell failure. This might lead to a clearer work.’’ advantage of these structural studies for link between organismal aging and telo- a clinical application to dyskeratosis meres, she says. ‘‘I’m not a believer that Regina Nuzzo, Science Writer

1. Chen, J.-L. & Greider, C. W. (2005) Proc. Natl. Bacchetti, S. (1992) EMBO J. 11, 1921–1929. 9. Chen, J.-L., Blasco, M. & Greider, C. W. (2000) Acad. Sci. USA 102, 8080–8085. 6. Blasco, M. A., Funk, W., Villeponteau, B. & Cell 100, 503–514. 2. Greider, C. W. & Blackburn, E. H. (1985) Cell 43, Greider, C. W. (1995) Science 269, 1267–1270. 10. Chen, J.-L., Opperman, K. K. & Greider, C. W. 405–413. 7. Feng, J., Funk, W. D., Wang, S.-S., Weinrich, S. L., (2002) Nucleic Acids Res. 30, 592–597. 3. Greider, C. W. & Blackburn, E. H. (1989) Nature Avilion, A. A., Chiu, C.-P., Adams, R. R., Chang, 11. Hackett, J. & Greider, C. W. (2001) Cell 106, 337, 331–337. E., Allsopp, R. C., Yu, J., et al. (1995) Science 269, 275–286. 4. Harley, C. B., Futcher, A. B. & Greider, C. W. 1236–1241. 12. IJpma, A. & Greider, C. W. (2003) Mol. Biol. Cell (1990) Nature 345, 458–460. 8. Blasco, M. A., Lee, H.-W., Hande, P. M., Samper, 14, 987–1001. 5. Counter, C. M., Avilion, A. A., LeFeuvre, C. E., E., Lansdorp, P. M., DePinho, R. A. & Greider, 13. Hemann, M. T., Strong, M., Hao, L.-Y. & Greider, Stewart, N. G., Greider, C. W., Harley, C. B. & C. W. (1997) Cell 91, 25–34. C. W. (2001) Cell 107, 66–77. BIOCHEMISTRY

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