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Unlocking Immortality: Elizabeth Blackburn's Nobel Journey Through Telomeres

From describing oneself as a “lab rat” to transforming into an adventurer in the fields of  health and public policy. She uncovered the molecular structure of telomerase and participated in the discovery of the enzyme telomerase, a very crucial element in understanding cellular division and DNA replication. She is Elizabeth Blackburn. Her studies offer promise for cancer treatments, insights into the aging process, and potential links between life circumstances and lifespan. Blackburn stresses the importance of basing conclusions on solid data in all her pursuits. 


(Elizabeth Blackburn on the right and her sister ready for first day of school in Launceston, Tasmania; Image credit: The Nobel Prize)


Born in 1948 from Tasmania, Blackburn is a child of two medical professionals and the second among seven. Throughout her youth, she found herself fascinated by the natural world, from the jellyfish dotting the shoreline to the tadpoles she carefully observed in glass containers. Simultaneously, she was enamored by the allure of scientific exploration, immersing herself in the biography of Marie Curie repeatedly. As her bedroom was sullied with sketches depicting amino acids, she was full of passion and fascination towards the intricacies of molecular structures. 


In 1961, Leonard Hayflick observed a phenomenon known as replicative senescence or the Hayflick limit, revealing that human cells have a finite ability to divide when cultured outside the body (Hayflick, 1998). This limit is tied to telomeres, protective caps at the ends of chromosomes. In the 1970s, Alexei Olovnikov linked this limit to the replication of telomeric DNA, proposing that a terminal gap at the 5' end of telomeres couldn't be filled during DNA replication, leading to their progressive shortening with each cell division cycle (Olovnikov, 1971, 1973). James D Watson also recognized this issue, termed the 'end-replication problem'. Eventually, telomeres become critically short, triggering pathways for cellular senescence and death (Watson, 1972; Hermann et al., 2001; Samper et al., 2001).


In the late 1970s, Blackburn and her team made significant strides in understanding telomeres in Tetrahymena thermophila (Dancis and Holmquist, 1979). They noted variations in telomere length and observed that their elongation during extended cell growth was consistently linked to an increase in hexanucleotide repeats (Blackburn and Gall, 1978). Their research proposed a new mechanism for telomere replication, suggesting the involvement of a terminal transferase-like activity capable of adding telomeric repeats on chromosome ends (Szostak and Blackburn, 1982). Carol W Greider's work in 1985 further validated this notion by demonstrating such an activity in Tetrahymena cell-free extracts (Blackburn and Gall, 1978). This led to the identification and characterization of telomerase as a ribonucleoprotein complex, marking a pivotal moment in telomere research and revolutionizing our understanding of chromosome maintenance and cellular aging.


Tetrahymena thermophila, commonly known as pond scum. Elizabeth Blackburn uses these single-celled organisms in her study of telomeres (Image credit: Robinson R (2006) Ciliate Genome Sequence Reveals Unique Features of a Model Eukaryote.)


Telomerase's importance extends beyond Tetrahymena, serving as the primary mechanism for telomere elongation across eukaryotes. Studies in yeast and mammals underscore its essential role in preserving telomere length, as its absence results in accelerated telomere shortening, premature aging, and diminished longevity in mice (Cooper et al., 1997). While alternative mechanisms for telomere maintenance exist, such as ALT in mammals, they fall short in sustaining organismal fitness and propagation (Schoeftner and Blasco, 2008).


Telomeres, akin to protective tips on shoelaces for our chromosomes, consist of repetitive DNA sequences shielded by specialized proteins. As we age, these telomeres naturally degrade, rendering chromosomes vulnerable. When telomeres fail to safeguard chromosomes effectively, cells lose their ability to replenish and start malfunctioning. This initiates physiological alterations in the body, elevating the risk of various age-related conditions such as cardiovascular disease, diabetes, cancer, and weakened immune function (Flores et al., 2005; Hao et al., 2005). However, this process isn't fixed; it varies among individuals and can be influenced by factors like lifestyle. Telomerase, an enzyme, can counteract telomere shortening by adding DNA to chromosome ends, potentially slowing down, preventing, or even partially reversing the aging process.


As we all possess health spans, indicating the duration of our healthy, active, and ailment-free years. The shortening of telomeres plays a role in aging, marking the transition from the health span to the disease span (Harley, 2008). However, certain practices can influence telomerase activity and telomere length, potentially postponing the onset of the disease span. Thus, the focus lies on prolonging overall health and fending off age-related ailments rather than drastically extending life expectancy. Nonetheless, maintaining better health for longer does correlate with lower mortality rates.


In 1990, Blackburn relocated her laboratory to UCSF, where she and her team embarked on a quest to unravel the intricate interplay between the protein and genetic constituents of telomerase as explained in The Nobel Prize website. They aimed to decipher how cells maintained a delicate equilibrium between telomerase's potential for excessive activity, posing a risk of cancer, and insufficient activity, resulting in chromosome shortening and cellular demise. Collaborating with psychologist Elissa Epel in the early 2000s, they investigated telomere length in caregivers of chronically ill children, spouses of dementia patients, and individuals with a history of early trauma (Corey, 2009). Their findings were unequivocal: prolonged exposure to chronic stress correlated with shorter telomeres, suggesting that stress could accelerate cellular aging.


This research resonated deeply with Blackburn, particularly as a mother, prompting her to empathize with the women involved. Despite its personal significance, it raised intriguing questions about the intersection of stress and telomere length.


Elizabeth Blackburn (center) in her lab with Beth Cimini (left) and Mike Pollard (right) (Image credit: The Nobel Prize)


Continuing her inquiry, Blackburn now explores whether lifestyle factors like exercise and meditation can elongate telomeres and slow cellular aging. She also investigates how adverse childhood experiences, such as growing up in war zones or poverty, impact telomere length. Additionally, she explores whether a mother's social disadvantage can influence her child's telomere length, thus shedding light on intergenerational health disparities (Zoe Corbin, 2018). While Blackburn's inquiries transcend the confines of the laboratory, she consistently reverts to the lab to find answers. She upholds rigor in her methodologies and exercises caution in her conclusions.

 

Article prepared by: Nur Anis Afifah Mohd Elias, Research and Development Associate of MBIOS 23/24


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References


  1. Am, O. (1971). [Principle of marginotomy in template synthesis of polynucleotides]. PubMed, 201(6), 1496–1499.

  2. Blackburn, E. H., & Gall, J. G. (1978). A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. Journal of Molecular Biology, 120(1), 33–53. https://doi.org/10.1016/0022-2836(78)90294-2

  3. Cooper, J. P., Nimmo, E. R., Allshire, R. C., & Cech, T. R. (1997). Regulation of telomere length and function by a Myb-domain protein in fission yeast. Nature, 385(6618), 744–747. https://doi.org/10.1038/385744a0 

  4. Corey, D. R. (2009). Telomeres and Telomerase: From Discovery to Clinical Trials. Chemistry & Biology, 16(12), 1219–1223. https://doi.org/10.1016/j.chembiol.2009.12.001 

  5. Dancis, B. M., & Holmquist, G. P. (1979). Telomere replication and fusion in eukaryotes. Journal of Theoretical Biology, 78(2), 211–224. https://doi.org/10.1016/0022-5193(79)90265-0 

  6. Flores, I., Benetti, R., & Blasco, M. A. (2006). Telomerase regulation and stem cell behaviour. Current Opinion in Cell Biology, 18(3), 254–260. https://doi.org/10.1016/j.ceb.2006.03.003 

  7. Harley, C. B. (2008). Telomerase and cancer therapeutics. Nature Reviews Cancer, 8(3), 167–179. https://doi.org/10.1038/nrc2275 

  8. Hayflick, L. (1998). A Brief History of the Mortality and Immortality of Cultured Cells. The Keio Journal of Medicine, 47(3), 174–182. https://doi.org/10.2302/kjm.47.174 

  9. Hemann, M. T., Strong, M. A., Hao, L.-Y., & Greider, C. W. (2001). The Shortest Telomere, Not Average Telomere Length, Is Critical for Cell Viability and Chromosome Stability. Cell, 107(1), 67–77. https://doi.org/10.1016/s0092-8674(01)00504-9 

  10. Lee, H. W., Blasco, M. A., Gottlieb, G. J., Horner, J. W., Greider, C. W., & DePinho, R. A. (1998). Essential role of mouse telomerase in highly proliferative organs. Nature, 392(6676), 569–574. https://doi.org/10.1038/33345 

  11. Olovnikov, A. M. (1973). A theory of marginotomy. Journal of Theoretical Biology, 41(1), 181–190. https://doi.org/10.1016/0022-5193(73)90198-7 

  12. Robinson, R. (2006). Ciliate Genome Sequence Reveals Unique Features of a Model Eukaryote. PLoS Biology, 4(9), e304. https://doi.org/10.1371/journal.pbio.0040304

  13. Samper, E., GoytisoloF. A., Josiane Ménissier‐de Murcia, González‐Suárez, E., Cigudosa, J. C., Gilbert de Murcia, & BlascoM. A. (2001). Normal telomere length and chromosomal end capping in poly(ADP-ribose) polymerase–deficient mice and primary cells despite increased chromosomal instability. Journal of Cell Biology, 154(1), 49–60. https://doi.org/10.1083/jcb.200103049 

  14. Schoeftner, S., & Blasco, M. A. (2009). A “higher order” of telomere regulation: telomere heterochromatin and telomeric RNAs. The EMBO Journal, 28(16), 2323–2336. https://doi.org/10.1038/emboj.2009.197 

  15. Szostak, J. W., & Blackburn, E. H. (1982). Cloning yeast telomeres on linear plasmid vectors. Cell, 29(1), 245–255. https://doi.org/10.1016/0092-8674(82)90109-x

  16. Watson, J. D. (1972). Origin of Concatemeric T7DNA. Nature New Biology, 239(94), 197–201. https://doi.org/10.1038/newbio239197a0 

  17. Zoë Corbyn. (2018, March 21). Elizabeth Blackburn on the telomere effect: “It’s about keeping healthier for longer.” The Guardian; The Guardian. https://www.theguardian.com/science/2017/jan/29/telomere-effect-elizabeth-blackburn-nobel-prize-medicine-chromosomes 

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