The Nobel Prize for Medicine for Telomere Biology and Relevance to Heart Failure Research

On 5 October 2009, the Nobel Assembly at the Karolinska Institute announced that they had decided to award the Nobel Prize in Physiology or Medicine 2009 jointly to Elizabeth H. Blackburn, Carol W. Greider, and Jack W. Szostak for the discovery of ‘how chromosomes are protected by telomeres and the enzyme telomerase’. These discoveries had a major impact in the field of cellular biology, especially in the field of the ageing process and cancer research. In the present commentary, we aim to put this discovery into a historical perspective and elaborate on its potential relevance for the clinical condition of chronic heart failure (CHF). Alexis Carrel, Nobel Prize winner in Physiology or Medicine in 1912, was convinced that all cultured explanted cell are immortal.1 He was convinced that failure to cultivate primary cells infinitively was due to ignorance on how best to cultivate cells. In the 1960s, this statement made it difficult for Leonard Hayflick to publish his correct findings that a cell could only divide about 50 times before entering senescence(definition). His observation was rejected by the prestigious Journal of Experimental Medicine and he received back a noteworthy comment from the editor: ‘The largest fact to have come from tissue culture in the last fifty years is that cells inherently capable of multiplying will do so indefinitely if supplied with the right milieu in vitro’.1 Later the manuscript was published by Experimental Cell Research.2 Currently this manuscript has been cited ~3500 times (only one in ~135 000 articles are cited more) and the described phenomenon is currently referred to as the ‘Hayflick limit’. The location of the counting mechanism (or replicometer) was discovered to be within the nucleus by Woodring Wright, a doctoral student in Hayflick's laboratory. Around 1971, James D. Watson hypothesized that because of the nature of lagging-strand synthesis, DNA polymerase cannot completely replicate the 3′ end of linear duplex DNA. At the same time, the Russian theoretical biologist Olovnikov realized that the repeated shortening of the DNA molecule at each round of DNA replication might explain Hayflick's findings. In 1978, Elizabeth H. Blackburn was the first to discover the sequence of the terminal end of the chromosome in Tetrahymena thermophila, thereby launching the field of telomere(definition) research (Figure 1).3 The telomere ends appeared to be cross linked at their termini, but it remained difficult to distinguish between true hairpin terminus and other forms of cross links. In 1982, Jack W. Szostak and Blackburn together reported that the terminal restriction fragment of the Tetrahymena rDNA plasmid can function as a telomere and protect linear plasmid DNA when introduced in yeast.4 These experiments provided new insights into the structure and function of telomeres and their highly conserved nature. The next major breakthrough in telomere biology was the discovery of the enzyme capable of building telomeres and restoring telomere length even after a cell division. In 1985, the enzyme named reverse transcriptase telomerase was discovered by Carol W. Greider, who was working as a post-doctoral student at that time in Blackburn's laboratory.5 The enzyme telomerase has a RNA template and is capable of elongating the telomeres and is essential for maintaining telomere length for offspring (Figure 2). In 1997, Maria Blasco and Greider created the telomerase deficient mouse, providing a model to study telomere biology in more detail.6 Only last year the paradigm that telomeres are transcriptionally silent was broken when the telomeric repeat-containing RNA (TERRA) was discovered. Telomeric repeat-containing RNA is an in length heterogeneous non-coding RNA transcript that binds to components of the telomeric structure.7 The sequence of TERRA is complementary to the TERC template of telomerase and it has been suggested TERRA might be involved in regulation of telomerase activity and consequently telomere length. Nevertheless, the exact function of TERRA remains to be elucidated. The incidence and prevalence of CHF increases markedly with advancing age but the susceptibility to develop heart failure remains highly variable and cannot be explained by the presence of conventional risk factors.8 An accumulation of age-associated changes might play a role in increased susceptibility to develop CHF during ageing. The molecular mechanisms involved are thought to include free radicals, advanced glycation end-products, apoptosis, and senescence among others. The process of telomere erosion has recently been put forward as a mechanism that runs parallel with ageing and the increased susceptibility to develop CHF.9,10 However, cause and consequence for the reported associations with telomere length and CHF remain to be determined. On one hand, genetically determined telomere length and increased attrition due to stressors might be causally involved in CHF. On the other hand, changes related to the development of CHF may in parallel cause telomere attrition or CHF itself might cause telomere attrition. Several lines of evidence suggest a role of telomere biology in CHF. For example, in apparently healthy elderly subjects, shorter telomere length is related to reduced left ventricular ejection fraction.11 Telomere length has also been related to several factors known to increase the likelihood of expressing signs and symptoms of CHF. The presence of hypertension, diabetes mellitus, atherosclerosis, and activation of the renin–angiotensin–aldosterone system have all been associated with reduced telomere length9,12,13. Indeed, subjects with CHF not only have shorter telomeres compared with healthy controls but telomere length is also related to the severity of symptoms.14 We recently reported that CHF subjects with shorter telomeres are at an increased risk for heart failure hospitalization and death.15 Within CHF subjects, reduced telomere length is related to characteristics known to be