Barbara McClintock, an American cytogeneticist, while working with x ‘ray effects on chromosomes of fruit fly, noted that the ends of the chromosomes known as ‘Telomeres ‘( Greek Telo -meaning “end & “ mere -meaning “Part “) are strangely resistant to mutagenic effects of x ‘rays and therefore postulated that they are different from the body of the chromosomes which become sticky and suffer destruction when subjected to X rays . They later concluded that part located at the ends of the chromosomes must have different structure and function, much like the shoe-laces have plastic caps at the ends which seal and protect the shoe laces. Barbara McClintock got the Nobel prize for physiology or medicine in 1983.
With each cell division the Telomeres become shorter but they regain their length with the help of Enzyme Telomerase only up to a critical number of such cell divisions. Once that critical number of cell division is reached which is different for different tissue cells, the telomere length is not restored thus reflecting the onset of ageing process and eventual death.
This provides yet another tool to understand and measure the process of ageing or senescence. It opens up treatment windows for incurable genetic diseases such as Dyskeratosis congenita , Congenital Aplastic anaemia, Liver cirrhosis and Lung fibrosis.
To the contrary ,Cancer cells which are characterised by unlimited capacity to divide and grow has abundance of enzyme “Telomerase “which help regenerate the telomere at each cell cycle indefinitely. Therefore by limiting the amount of enzyme ‘Telomerase ‘it may in future control and treat the dreaded Cancer .
Drs. Elizabeth H .Blackburn, Jack W. Szostak and Carol W. Greider - all three were awarded Nobel prize in physiology or medicine in 2009 for their discovery of how chromosomes are protected by mysterious ‘Telomeres’ and it’s associated enzyme ‘Telomerase’.
James Watson and Crick who had wonderfully resolved the intricate structure of DNA molecule suggesting a double helix architecture for DNA for which they were awarded Nobel prize in 1962 ,had hinted about the end part of chromosomes which according to them behaved differently than the rest of the chromosomes .
Every time the chromosomes are copied for creating the next DNA strand , it becomes a little shorter. This end replication problem remained an unresolved question!
Elizabeth Blackburn, a cell biologist who migrated from Australia to USA in search of better research facilities, came across single cell organism called ‘Tetrahymena ‘a pond scum, which has many short linear DNA sequences in its mini chromosomes the end of which had unique short DNA sequence repeated twenty to seventy times. This was a chance observation.
Jack Szostak ,who was working at Harvard university for years on preparing ‘Artificial DNA sequencing ‘was facing problems and was unable to add his synthesised DNA sequence to the yeast ( different from pond scum ) chromosomes and make it grow . He approached Blackburn to see if her mystery loaded specific DNA ( ?Telomeric )sequence could help the ‘artificial DNA Sequence’ to integrate to the yeast chromosomes to stabilise and multiply . This turned out to be a surprise success and thus his decade long hard work paid off with an extra dose of serendipity. That led to the birth of the famous ‘Telomere’. Surprisingly, such chromosomal end structures - the “Telomere “have been preserved in all eukaryotic cells (cells with nucleus) including human beings through the billions of years of evolution.
Yet another unique observation struck brilliant Dr Blackburn and Dr Szostak while they were analysing the chromosomes which were left in yeast culture for a longer period. To their utter surprise they found that these telomeres grew longer and longer with passage of time suggesting some extra enzyme presence.
Enzymes that copy the DNA - ‘ DNA polymerase’ was well known for their function but now they had a suggestion for the presence of one more enzyme that get added to the existing chromosomes to help telomeres grow .
Carol Greider, a 23 year old doctoral student working in university of California, Berkley under Dr Blackburne prepared an extract of “Tetrahymena yeast cells “ and added to it a mixture of short telomere DNA sequences and radioactively tagged nucleotides ( the units which make the DNA) to the yeast cell culture. Surprisingly they found that the nucleotides were securely attached to the existing Chromosomal chain suggesting the presence of that new enzyme which was aptly named as “Telomerase “ which could help integrate with the main body of chromosomal DNA ‘ and extend its length . Therefore, it was concluded that it is the enzyme ‘Telomerase ‘whose absence leads to ageing in senescent cells and excessive presence leads to unlimited growth of cancer cells thus opening entirely a new vista of genetics and cancer biology.
Telomeres have attracted the attention of scientists as a tool and a reliable and accurate mirror of Health as well as longevity. For example Aerobic exercise of even half an hour for a month has been seen to increase measurable Telomere length and intense stressful bereavement of weeks to the contrary, is documented to shorten Telomere length!
Only very recently In April 2020 a sensational breakthrough from Harvard USA found lead space in journal ‘ Cell Stem cell” authored by an Indian researcher Dr Neha Nagpal ,who has developed a molecule called PAPD5 inhibitors-BCH001 , with great potential to reverse the depleted Telomerase enzyme and thus reverse ageing of different tissues and several disease states such as untreatable Duskeratosis congenita .
Telomere research has thus introduced a fundamental change in understanding the intricacies of cell biology and has opened an entirely novel field with vast potential.
The author is former Professor and Head of Medicine, RIMS, Ranchi.
