Series: Sciencious Medical Writing Conference
One of the hardest diseases to treat in the modern era is cancer, a powerful foe that has attacked civilization for generations. Finding effective treatments is a constant struggle because of its complicated makeup and ability to mutate. But in the middle of the never-ending search for a treatment, a revolutionary approach has arisen, giving millions of individuals suffering from this deadly illness a new hope.
The solution is related to DNA replication. For the linear DNA in human body, the usual replication machinery cannot complete the 5′ ends of daughter DNA strands, this is a consequence of the fact that DNA polymerase can add nucleotides only in the 3′ end of a pre-existing polynucleotide sequence. For the DNA strand which is 3′ to 5′ direction, RNA primers involve and bind to the DNA strand so it is considered as a 5′ beginning for the DNA polymerase to start from and add nucleotides, once it reaches the end, other RNA primers attaches next to the first ones and then the same process happens repeatedly till the end of replication causing numerous fragments called “Okazaki Fragments“. Here comes the problem, even if an Okazaki fragment can be started with an RNA primer bound to the very end of the DNA strand, once that primer is removed, it cannot be replaced with DNA nucleotides because there’s no 3′ end available for nucleotide addition.
As a result, repeated rounds of DNA replication produce shorter and shorter DNA molecules with uneven ends. This may cause some essential genes to be eroded by the time which may cause the cell disfunction and maybe death. But this actually doesn’t happen, fortunately, eukaryotic chromosomal DNA molecules such as human’s DNA contain special nucleotide sequences called “Telomeres” at the tips of each chromosome. Telomeres do not contain genes, instead, they consist of multiple repetitions of one short nucleotide sequence. Actually, telomeres do not prevent the shortening of the DNA or prohibit the erosion of genes near the ends of chromosomes, instead, they postpone it, you can think of it like how the plastic-wrapped ends of a shoelace slows its unravelling.
Telomeres become shorter after every round of DNA replication, and thus, telomeric DNA tends to be shorter and shorter after every cell division for somatic cells and cultured cells that have divided multiple times. This would affect cells whose genome must persist unchanged from an organism to its offspring for several generations, because if the chromosomes of germ cells become shorter in every cell cycle, essential genes will be missing in the gametes they form. But again, this doesn’t occur, an enzyme called “Telomerase” catalyses the lengthening of telomeres in eukaryotic germ cells, thus restoring their original length and compensating for the shortening which occurs during DNA replication. Normal shortening of telomeres may protect organisms from cancer as it limits the number of cell divisions a cell can undergo.
Telomerase Inhibition Treatment
Telomerase is present in all human body cells but it is not active in all the cells, in other words, it is silenced in all the cells except for germ cells (the cells which produce sperms and eggs) and some adult stem cells. For cancer cells, telomeres are unusually short as expected for cells that have undergone numerous cell divisions, thus, telomerase activity is abnormally high, its ability to stabilise telomere length allows the persistence of those cancer cells which make them seem capable of unlimited cell divisions. And so, the treatment is in inhibiting telomerase activity in cancer cells, because further shortening in telomeres will lead to the self-destruction of the tumor cells and apoptosis (cell death). Further research has been conducted in this field, and studies that inhibited telomerase in mice with tumors have led to the death of cancer cells, restoring the normal cells with their normal telomeres’ length.
Telomerase can be inhibited in many ways, and the best way is by targeting the RNA component of telomerase, “antisense oligonucleotides” can be inserted so it eliminates
telomerase activity. It is noteworthy to mention that “imetelstat” is the only direct telomerase inhibitor that has entered clinical trials. And based on this data, telomerase inhibition appears to be the most effective cancer treatment.
– Reece, J. B., & Campbell, N. A. (2011). Campbell Biology. Pearson Learning Solutions.
– Cunningham, A. P., Love, W. K., Zhang, R. W., Andrews, L. G., & Tollefsbol, T. O. (2006). Telomerase inhibition in cancer therapeutics: Molecular-based approaches. Current medicinal chemistry.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423208/#:~:text=Antisense%20a nd%20Related%20Oligonucleotides,commonly%20used%20since%20the%20199 0s.
– Khan Academy. (n.d.). Telomeres and telomerase (article). Khan Academy. https://www.khanacademy.org/science/biology/dna-as-the-genetic-material/dna-re plication/a/telomeres-telomerase#:~:text=Telomerase%20is%20not%20usually%2 0active,and%20some%20adult%20stem%20cells.
– Neha J. Pancholi, P. (2022a, September 17). The end game: Targeting telomere processing in cancer . American Association for Cancer Research (AACR). https://www.aacr.org/blog/2022/09/16/the-end-game-targeting-telomere-processin g-in-cancer/#:~:text=In%20mouse%20models%2C%20imetelstat%2Dmediated,wi th%20certain%20rare%20hematologic%20cancers.
– Beaubien, J. (2014, February 5). Cancer cases rising at an alarming rate worldwide. NPR. https://www.npr.org/sections/health-shots/2014/02/04/271519414/global-cancer-ca ses-rising-at-an-alarming-rate-worldwide
– Image: https://www.europeanpharmaceuticalreview.com/article/177232/the-promise-of-telomerase-inhibitors-for-treating-blood-cancer/