Controlled telomerase
How does the machine of immortality work
Alexey Aleksenko, "Snob"
Biologists have clarified the details of the mechanism by which, over 4 billion years of evolution, none of the cells from which you came did not die, but kept dividing and dividing, right up to your very birth.
In fact, this story is about the enzyme telomerase, not about immortality. It was one of the mysteries of telomerase that was revealed by the recent scientific work of Professor Julian Chen from the University of Arizona and his colleagues (A single nucleotide incorporation step limits human telomerase repeat addition activity, The EMBO Journal, 2018). And what about immortality? Immortality does not exist – except in one very specific sense.
Every cell in your body is a product of the division of another cell. All of them came from one mother's egg, which turned out in a few dozen divisions from your grandmother's fertilized egg, and that one from your great–grandmother's egg. Further in this row were the eggs of pithecanthropus, monkeys, some obscure Mesozoic rats...
Just imagine that for hundreds of millions of years these cells were hiding in the dark and moist depths of the gonads, none of them saw sunlight until you personally hatched from the last one. Further into the past are the cells of Devonian salamanders and Silurian fish (these have already seen the light, being caviar at some point in their lives). Then - Ediacaran worms, sponges, flagellates, microbes... The lineage of your body's cells goes back 4 billion years, and each of their ancestral cells was divided in two at the appointed hour. None of them died, or you wouldn't have been there.
Nevertheless, all the cells of your body are almost guaranteed to die – except perhaps a few milligrams of living matter located in the lower part of the trunk and intended for procreation. Still, however, an unpleasant scenario is possible when biologists will take a sample of malignant tissue from you and will forever cultivate it in the laboratory. But this only illustrates the thesis "we are all mortal."
What is the difference between the mortal cells of your body and the series of immortal cells from which they originated? One of the differences is the enzyme telomerase, discovered in 1984. Jack Shostak, Elizabeth Blackburn and Carol Greider received the Nobel Prize for this. But the fact that such an enzyme must necessarily be found has been guessed since the early 1970s. And here's why.
In the DNA double helix, two strands run in opposite directions, like trains in the subway: if you look at the molecule from the end, the front spotlight of hydroxyl will glow on one strand, and the red brake light of phosphate on the other. When DNA doubles, the new chain grows only in the direction where the spotlight shines. To copy both chains, you need small seeds with hydroxyl projectors sticking out of them, which are later removed, and the whole structure restores its former beautiful appearance. This scheme works fine in ring molecules. But – you can take a pencil, or you can take my word for it – a linear molecule has no way to correctly reproduce a few letters at the very end.
Schematic representation of the replication process, numbers are marked: (1) Lagging strand, (2) Leading strand, (3) DNA Polymerase (Pola), (4) DNA ligase, (5) RNA Primer, (6) Primase, (7) Okazaki fragment, (8) DNA-Polymerase (Polδ), (9) Helicase, (10) Proteins binding single-stranded DNA, (11) Topoisomerase.
Mariana Ruiz, Wikipedia.
Therefore, with each doubling, the molecule will shorten slightly. This means that no cell could have lived for hundreds of millions of years, comfortably dividing and thriving, if nature had not had some special way in reserve to restore the mutilated ends of chromosomes. This is what telomerase does.
Illustration: Arizona State University
Telomerase is a protein that contains an RNA molecule. From this RNA, a dull repeating motif of six letters is read, decorating the ends of all your chromosomes: GGTTAG, and then again and again. It is present in all cells of the body, and most cells do not need to complete it: there are enough repeats that the cell inherited from the embryo stage. There is no telomerase there, and there is no need. The ends of the chromosomes, of course, shorten with each division, but it is not a sin to shorten such a meaningless sequence. And then old age and death come anyway.
However, telomerase regularly does its job in germ cells, that is, germ line cells, so that your family can, at least theoretically, continue indefinitely into the future. And it also works little by little in those tissues that are destined to survive especially many cell divisions during your lifetime. For example, in stem cells. The trouble is that it doesn't work too well there for some reason. That is, much slower than it could theoretically be. Probably, if we make her work harder, stem cells will be much more durable, and we ourselves will live longer and happier. But to do this, we must first understand what is wrong with our telomerase. This is what Julian Chen did.
Professor Chen found a brake on telomerase. How does it work? If our reader happens to be a biologist, we recommend him to refer to the original article: the word artist who can explain molecular biological processes without drawing squares and wavy lines on the blackboard has not yet been born. If the reader is an ordinary person, then this is what telomerase does: by joining the end of the chromosome, it very quickly attaches the first three letters to it. But something clicks on the letter T there inside; the machine goes through three more letters by inertia and stops for a long time. The brake worked. It remains pressed even when the typewriter moves six letters forward and repeats the cycle.
Chen found this brake three years ago, and now he has learned how to control it. It turned out that it was easier to let go of the brakes of telomerase: you just have to give it more of the letter G (the very first letter of each repetition), feed it with guanidine triphosphate. Then our machine accelerates to a normal speed, with which a decent DNA polymerase should work.
Why is it necessary to slow down such a good, kind machine that provides immortality to at least some of our cells? Apparently, no one really needs telomerase to build up the ends of chromosomes day and night, unable to stop. It's easy to imagine what nonsense she could turn our precious genome into. Actually, without this brake, she would not have limited herself to the notorious six letters, but would have rushed to copy her own RNA without stopping, immensely darkening our lives (it's not for nothing that this machine came from a selfish ancient virus). But even if she doesn't rampage, but just does her job, it won't necessarily benefit us at all. In cancer cells, for example, telomerase often works at full capacity. Yes, these cells are immortal, as we have already mentioned here. The trouble is that because of them we sometimes die prematurely, but we don't want that at all.
And yet, in some cases, it will be useful to spur telomerase. For example, our stem cells in some cases do not prevent to cheer up and forget about age. Many serious diseases – congenital dyskeratosis, aplastic anemia, idiopathic pulmonary fibrosis – are accompanied by accelerated damage to chromosomal tips in certain types of cells. Probably, now that the telomerase brakes have been disassembled, it will be easier for researchers to develop drugs that will help correct such situations. If we have an immortality machine and if it brings immortality not to us personally, but to some kind of "germ line cells" living in complete darkness and knowing nothing about life, we should get at least some benefit from it. Presumably, for the sake of this, Professor Julian Chen clung to this telomerase and learned so much about it.
This article was published in the weekly "Windows", a literary supplement to the Israeli newspaper "Vesti" www.vesti.co.il
Portal "Eternal youth" http://vechnayamolodost.ru