By Danielle Medina
Carol Greider, a distinguished molecular biologist and Nobel Laureate, is driven by an unwavering curiosity for the intricate world of DNA. Her journey began with an initial pursuit of Marine Biology, indulging in her love for scuba diving. Yet, a pivotal molecular biology class ignited her passion for science, paving the path to her groundbreaking discoveries and eventual Nobel Peace Prize in Physiology or Medicine. Her career in molecular biology began at UC Santa Barbara, where she pursued an undergraduate degree in Marine Biology. There, Greider simultaneously indulged her passion for marine studies and ignited a newfound interest in complex niches of science, specifically molecular biology. Her curiosity and steadfast interest in the subject during her undergraduate years paved the way for Greider’s groundbreaking discoveries in molecular biology, including her eventual Nobel Prize win in 2009. After completing her undergraduate degree at UCSB, Greider furthered her education at UC Berkeley in the Molecular Biology Department. Greider states that she has always been drawn to information concerning topics not widely understood. Grieder compares research to “riding a surfboard,” as her curiosity for the unknown has taken her to many different fields in biology. Comparing “the water underneath you” to different biological fields, yet her passion, her “board,” remains the same. In 1984, Grieder became fascinated with a lesser-known segment of the chromosome: the Telomere. Her curiosity about Telomeres initiated her path to the discovery of the enzyme, Telomerase. This discovery led to one of Dr. Greider’s most defining moments: being awarded the Nobel Prize in Physiology or Medicine. Only after the birth of her children had she ever experienced similar elation. She describes, however, that this discovery did not occur overnight. First, it took approximately seven days of experimentation to determine a “pattern on a radiogram that suggested there was an enzyme that was adding sequences onto the end of chromosomes.” It then took another year to determine that this pattern was not “coming from something other than what we thought.” Grieder’s discovery of an unfamiliar enzyme sparked discussions with colleagues who realized it matched the enzyme they had been searching for: Telomerase. It was then that Grieder and her colleague Elizabeth H. Blackburn published their paper Identification of a Specific Telomere Terminal Transferase Activity in Tetrahymena Extracts in Cell in December 1985. Grieder and Blackburn’s paper explores a remarkable behavior exhibited by Tetrahymena, a unicellular eukaryote. This organism “adds tandem TTGGGG repeats onto synthetic telomere primers” 1 . Greider and Blackburn focused on sequences derived from Tetrahymena and yeast telomeres. These sequences comprised single-stranded DNA oligonucleotides functioning as primers, along with DNA oligomers lacking primer activity. Employing distinct methodologies, the researchers conducted experiments using Tetrahymena extracts to isolate and characterize the enzyme responsible for telomere terminal transferase activity. They observed that this activity was susceptible to heat and proteinase K treatment. Notably, the addition of repeats at the DNA end was found to be unaffected by both endogenous Tetrahymena DNA and the alpha-type DNA polymerase 1 . At this point, researchers Greider and Blackburn introduced the concept of telomere terminal transference. This process entails the addition of repetitive nucleotide sequences at chromosome ends, which is vital for the replication of these structures in eukaryotes 1 . Initially termed "Telomere Terminal Transferase" due to its function in transferring telomere sequences to chromosome termini, the term was later shortened to "telomerase" 2 . In an article published in ScienceDaily, Greider's research exposes medical implications for too-short or too-long telomeres. Short telomeres are associated with age-degenerative diseases such as pulmonary fibrosis, bone marrow failure, and immunosuppression 3 . Conversely, long telomeres make one pre-disposed to cancer by promoting the growth of tumors 4 . A study conducted at Johns Hopkins University found that participants with a mutation in POT1, a telomere-linked gene, had longer telomere lengths 4 . These participants notably had colon cancer, melanoma, lymphomas, leukemia, enlarged goiters, uterine fibroids, and other cancers 4 . Grieder’s discovery of telomerase provided her with an invaluable lesson: instead of solely focusing on supporting a hypothesis, actively seek ways to disprove it. In her own words, “If you can’t shoot it down, then you have a strong hypothesis.” As Grieder’s journey continued, she found herself at Cold Spring Harbor Laboratory in Long Island, New York. Here, she met Bruce Stillman, who became one of her trusted colleagues. Bruce Stillman was among one of the individuals she would turn to during challenging times. Whenever she encountered an issue that required resolution, Stillman would promptly resolve it “right then.” Grieder was astonished that Stillman would never put off a situation to a later time, instead, he would resolve it as soon as it was brought to his attention. Grieder acknowledged that this method of resolving a problem was very effective and she incorporated it into her daily routine. Ten years after working at Cold Spring Harbor Laboratory, Grieder was recruited to John Hopkins University and became the Chair of the Department of Molecular Biology and Genetics. Here, she met her next positive influence: Dr. Tom Kelly. Kelly’s charismatic demeanor had a compelling effect, often endearing him to scientists and earning their admiration and respect. This captivated Grieder, leading to her incorporating the phrase What would Tom do? in her daily routine, elevating her work ethic.
Dr. Greider’s journey did not end there. In 2020, she came to the University of California, Santa Cruz where she is known as a Distinguished Professor and runs her own lab. The Greider Lab studies telomeres in yeast and human cells 5 . By studying telomeres in two different organisms, Greider states that she is able to determine “what are the things that might be affecting telomere length regulation” as well as if “those things regulate telomere length.” Dr. Greider formally teaches Molecular Biology, BIOL 101, to undergraduate students at UC Santa Cruz. Here, she teaches the basics of molecular biology and laboratory techniques, establishing a concrete foundation for undergraduates to build upon as they further their own scientific education. She also co-teaches Critical Analysis of Scientific Literature, BIOL 200A, with Professor Jordan Ward, where they dive into the analysis of meticulously picked research articles in the field of biology. Dr. Greider is also a mentor for her students in the lab and emphasizes that the majority of her teaching takes place there. She is a strong believer in the importance of observational learning, and advises that her students not only “pay attention to the really good talks” but also “pay attention to the really bad talks” when attending research conferences. These little details form the best structure for her students to take the first step into their careers.
While Grieder’s life may seem full of admirable and impressive accomplishments, it has come with a cost. In her line of work and at the level she performs, it makes it difficult to balance everyday life and her other responsibilities. When asked if work-life balance is achievable, Dr. Greider states that work-life balance is “not a thing” and compares work and personal life to a scale. Sometimes she may have work deadlines that are going to tilt the scale in one direction, or her kids' sickness tilts it in a different direction. Her “fear is that people [say] they want to have a work-life balance, they want it to always be [equally balanced] therefore [they are] never going to be happy.” Is this the reality of a scientist?
Although her work-life balance may still be in the works, her motivation for research is crystal clear. Even after working on telomeres for thirty-five years, Dr. Greider still finds excitement through new discoveries. This motivation drives her to keep studying telomeres and keep pushing for new grants and authoring papers seen in the likes of the Journal of Science. Dr. Greider recently published an article that focuses on the distribution of telomeres. Telomeres are maintained around a specific distribution and equilibrium, and in her paper, Dr. Greider states that “when distribution shortens, then you have age-related degenerative disease. If the distribution is too long, then you’re predisposed to cancer…on either side, if you aren’t maintained around distribution [equilibrium] there is disease.” Her findings emphasize how fundamental it is to understand how the distributions involving telomeres can be maintained. To further explore this, Dr. Greider started to use new technology that was invented at UC Santa Cruz, Nanopore Sequencing which is a new way to sequence DNA. The Greider Lab found that when looking at the distribution of all the chromosomes, “chromosome one has a very different length distribution than chromosome two, [which has a different distribution] than chromosome twelve. It’s not that there’s a distribution. It’s a whole bunch of different distributions.” By posing the question of how to establish a varied distribution across every chromosome end, it interferes with the known understanding. Exploring what influences these chromosomal end changes, may lead to a better understanding of the regulatory mechanisms. Dr. Greider hopes that this inquiry will yield meaningful insights.
These discoveries do come with their challenges. Dr. Greider kindly shared that after obtaining her best score on a grant proposal, she was still rejected by the funding officer. Research funding comes from the Federal Government, and in many instances, the budget is unclear. Therefore, it is hard to estimate how many research labs are funded. She noted that writing and rewriting grants is a “common thing” and that it is one of the many challenges that comes with being a scientist in the field.
Getting past the challenges, her discoveries impacted the field academically. Her discovery of Telomerase has become so mainstream that Dr. Greider says “Now telomerase is just a word, it’s like Kleenex or something.” No need for citation when using the word Telomerase. It has become a worldwide vocabulary word in the world of Biology. Dr. Greider says “If I got a citation number for every time somebody uses the word Telomerase, as opposed to every time they referenced it, it would be 1000 times more.” Nonetheless, Grieder is graciously humbled to see that Telomerase has become widely accepted in the scientific community. Dr. Greider envisioned her findings shaping the world of medicine, and it is evident that understanding the fundamentals of how telomere length influences age-related degenerative disease and cancer will provide new approaches for intervening in telomere regulation. This marks a significant stride towards gaining a deeper understanding of the medical field and achieving yet another scientific breakthrough.
Currently, Dr. Greider’s focus lies in understanding the regulation of telomere lengths specific to chromosome ends. She emphasizes the significance of examining the DNA sequences at these ends, comparing those with long telomeres to those with short ones. By swapping or juxtaposing telomeres, the question arises: “How does DNA replication affect telomere length?” This ongoing project continues to captivate as it unravels the answers to these pressing questions.
REFERENCES
1. Greider, C. W., & Blackburn, E. H. (1985). Identification of a specific telomere terminal transferase activity in tetrahymena extracts. Cell, 43(2), 405–413. https://doi.org/10.1016/0092-8674(85)90170-9
2. Carol W. Greider – Biographical. NobelPrize.org. Nobel Prize Outreach AB 2024. Tue. 21 May 2024.
https://www.nobelprize.org/prizes/medicine/2009/greider/biographical/
3. ScienceDaily. (2024, April 11). https://www.sciencedaily.com/releases/2024/04/240411165853.htm#:~:text=And%20that's%20important%20because%20of,and%20immunosuppression%2C%22%20Greider%20said.
4. Hopkins Medicine. (2023, May). https://www.hopkinsmedicine.org/news/newsroom/news-releases/2023/05/long-telomeres-the-endcaps-on-dna-not-the-fountain-of-youth-once-thought--scientists-may-now-know-why#:~:text=%E2%80%9CCells%20with%20very%20long%20telomeres,two%2Dyear%20Johns%20Hopkins%20study.
5. Groot, T. (n.d.). UC Santa Cruz MCDB. GreiderLab.https://www.greiderlab.org/
6. Carol Greider, Ph.D., Director of Molecular Biology & Genetics at Johns Hopkins University. Yale Dyslexia. (n.d.). https://dyslexia.yale.edu/story/carol-greider-ph-d/