Carol W. Greider

• Born: April 15, 1961

• AMERICAN MOLECULAR BIOLOGIST

Carol Greider was awarded the Nobel Prize in Physiology or Medicine in 2009 for her work in discovering the enzyme telomerase and identifying the role of telomeres in the maintenance of linear chromosomes.

• PRIMARY FIELD: Biology
• SPECIALTIES: Molecular biology; biochemistry; cellular biology

Early Life

Carolyn Widney Greider was born April 15, 1961, in San Diego, California, the second child of Kenneth and Jean Foley Greider. Both parents were scientists, her father having earned a PhD in nuclear physics and her mother a PhD in botany. Her parents were completing postdoctoral fellowships in San Diego at the time of her birth; they moved to New Haven, Connecticut, in 1962. In 1965, Greider’s father accepted a position in the department of physics at the University of California, Davis, and the family returned to California, where Greider spent her formative years.

In 1967, Greider’s mother committed suicide, exacerbating the difficulties Greider was facing in school. Among her challenges was an inability to sound out words, resulting in her placement in a remedial spelling class. It was only later that the problem would be recognized as a form of dyslexia. In 1971, Greider’s father took a sabbatical leave from Davis and moved to Heidelberg, Germany, where Greider and her brother, Mark, were enrolled in the Englisches Institut and where, by necessity, she learned German. Her dyslexia created problems at the school, particularly in her English classes, as she was unable to properly spell English words.

When she returned to California, Greider became increasingly interested in biology as she moved through both junior and senior high school, graduating from Davis Senior High School in 1979. Her decision to study science was particularly motivated by her twelfth-grade biology teacher. Greider’s father, who supported her love of reading, reminded her that a strong academic background would make available many opportunities in the future. Following high school graduation, Greider decided to enroll at the University of California, Santa Barbara (UCSB) in the College of Creative Studies.

Life’s Work

A friend of Greider’s mother, Beatrice “Beazy” Sweeney, was on the UCSB faculty and encouraged Greider to enroll in laboratory courses. In addition to aiding Sweeney with her studies of the movement of chloroplasts in a dinoflagellate, Greider also had the opportunity to work with other researchers in their studies of microtubule proteins.

Greider spent her junior year at the University of Göttingen in Germany, working with Klaus Weber at the Max Planck Institute. The biology class in which she enrolled provided the opportunity to study polytene chromosomes in Chironomus, an organism related to the fruit fly. In addition to giving her the chance to publish, Greider believed the work introduced her to an “appreciation for the beauty of chromosomes.” She graduated with a BS in biology in 1983.

Despite an outstanding undergraduate career, when it came time to apply for graduate admission, only two universities offered Greider interviews: the University of California, Berkeley and the California Institute of Technology. Once again, her dyslexia had proved a challenge when taking standardized tests, and her low scores precluded additional schools from accepting her applications. Greider met with biologist Elizabeth Blackburn at Berkeley during her interview and accepted an opportunity to work in Blackburn’s laboratory.

Blackburn had been attempting to characterize the sequence of nucleotide bases found on the tips of linear chromosomes, a region known as the telomeres, in the protozoan Tetrahymena. Blackburn and geneticist Jack Szostak had found evidence that the telomere sequences consisted of a series of bases repeated in tandem. Whether there was a specific enzyme that synthesized these units was unclear. Blackburn was convinced that a heretofore unidentified enzyme was involved, and Greider decided to pursue the question as part of her doctoral work once she became part of Blackburn’s group in May 1984.

While Greider and Blackburn quickly found indirect evidence of enzymatic activity, part of the challenge lay in differentiating activity associated with a DNA repair protein from that of the suspected telomere-producing enzyme. On December 25, 1984, they finally obtained definitive results: the enzyme that synthesized telomeres was a newly recognized protein not previously described. The enzyme was initially referred to as telomere terminal transferase, shortly renamed simply as telomerase. The work was published the following December.

Greider received her PhD in molecular biology in 1987, after which she joined the Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, on a postdoctoral fellowship. There, she continued with her research on telomeres and successfully cloned the gene that encodes telomerase. Following the successful application for a National Institutes of Health (NIH) grant, Greider was promoted to assistant investigator at the laboratory and was able to hire her first graduate student.

She also began collaborating with Calvin Harley from McMaster University in Ontario, Canada, who had been studying cellular senescence (cell aging) and its application to what was called a mitotic clock. Some twenty years earlier, cell biologist Leonard Hayflick had observed that cells could only replicate some fifty times before aging and death; cells from embryos could replicate dozens of times, while those obtained from an adult would barely replicate at all. The molecular basis for the clock was unknown. In contrast, transformed or cancer cells did not appear to be bound by such a clock, seeming to achieve immortality. Greider and Harley were able to demonstrate a relationship between telomere length and senescence: as chromosomes are replicated, the telomeres become progressively shorter, leading to senescence and death. They discovered that the gene-encoding telomerase is activated in cancer cells, suggesting a mechanism by which cancer cells become immortal.

Harley subsequently left academia for the biotechnology company Geron, headquartered in Menlo Park, California. For a time, Greider maintained her relationship with Harley, even joining the advisory board of Geron. However, she saw a conflict between the business side of research and the importance of public relations, as exemplified by Geron, and the academic pursuit of research for its own sake. Eventually, she broke with Harley and resigned from the advisory board.

In 1997, Greider accepted a position as an associate professor at the Johns Hopkins University School of Medicine in Baltimore, Maryland, where she continued her work on the characterization of telomerase and the implications of telomere formation in the malformation of stem cells. She later became the Daniel Nathans Professor of Molecular Biology and Genetics at the institute and then the director. In 2009, she, Blackburn, and Szostak were awarded the Nobel Prize in Physiology or Medicine for their work in characterizing telomeres and telomerase and identifying how they protect and maintain chromosomes. Greider was named a Bloomburg Distinguished Professor by Johns Hopkins in 2014. Eventually returning to California, she took a position as a professor of molecular, cell, and developmental biology at the University of California, Santa Cruz, in 2020. That same year, she was elected as a fellow of the National Academy of Inventors. In 2022, Greider was granted the Award for Excellence in Molecular Diagnostics by the Association for Molecular Pathology.

According to an article published by US Santa Cruz in 2024, a new study found that the length of telomeres follows a different pattern than Greider and her colleagues had initially believed. The length does not fall in the range of shortest to longest across all chromosomes. Instead, different chromosomes have different end-specific telomere lengths. Greider stated in the article that this discovery means that scientists do not yet fully understand the molecular process that determines telomere lengths. According to Greider, when telomere length is too short, individuals are predisposed to age-related degenerative diseases such as bone-marrow failure, immunosuppression, and pulmonary fibrosis. On the other hand, when telomere length is too long, people are predisposed to some kinds of cancer.

Greider married historian Dr. Nathaniel Comfort in 1992; they later divorced. She has two children.

Impact

The initial impact following the December 1985 publication of Greider’s work with Blackburn and Szostak was minimal. Many scientists, including both Greider and Blackburn, were not yet convinced their interpretation of telomere formation was correct. Ann Pluta and Virginia Zakian at the Fred Hutchinson Cancer Research Center in Seattle, Washington, for example, observed recombination events in telomere formation in yeast, an alternative explanation of synthesis. Further, telomeres were not yet sequenced in human cells at the time, so what had been observed in Tetrahymena might not have applied to human cells. It was only when others made similar observations, and when the presence of telomeres on the tips of chromosomes from other eukaryotic species, including humans, was observed, that the real significance of the discovery was recognized.

As Greider noted in the lecture she presented upon receipt of the Nobel Prize, the presence of telomeres in their repeating form across all ranges of species suggests that they arose early in evolution and have an important function within the cell. The question that remained was how the telomeres were produced, and it was here that Greider’s discovery was particularly important. The ability of Tetrahymenacell extracts to elongate telomeres in the yeast Saccharomyces suggested an unknown enzyme was involved; Greider’s discovery of that enzyme finally explained the mechanism of telomere formation.

Bibliography

Bartlett, Zane. "Carol Widney Greider (1961-)." The Embryo Project Encyclopedia, 26 Jan. 2015, embryo.asu.edu/pages/carol-widney-greider-1961. Accessed 15 Oct. 2024.

Brady, Catherine. Elizabeth Blackburn and the Story of Telomeres. Cambridge: MIT P, 2009. Print.

Lewis, Ricki. Discovery: Science as a Window to the World. Malden: Blackwell, 2001. Print.

Pena, Mike. "New Study Finds Potential Targets at Chromosome Ends for Degenerative Disease Prevention." US Santa Cruz, 11 Apr. 2024, news.ucsc.edu/2024/04/telomere-lengths.html. Accessed 17 Oct. 2024.

Stephens, Tim. "Biologist Carol Greider to Receive Award for Excellence in Molecular Diagnostics." UC Santa Cruz, 4 Oct. 2022, news.ucsc.edu/2022/10/greider-award.html. Accessed 15 Oct. 2024.

Stephens, Tim. "Eminent Biologist Carol Greider to Join UC Santa Cruz Faculty." UC Santa Cruz, 21 May 2020, news.ucsc.edu/2020/05/carol-greider.html. Accessed 15 Oct. 2024.

Wayne, Tiffany. American Women of Science since 1900. Santa Barbara: ABC-CLIO, 2011. Print.