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The long and short of Telomeres, Life and Death

Wednesday, September 12, 2012
Telomeres are like biological counters in DNA that control the number of times cells can divide. I learnt a lot of fascinating things about how these play a role in ageing, regeneration and death. And more I read, more my engineering mind found them similar to loop counters of computer programs. In today's post I discuss some fascinating trivia about telomeres as well as my analogies with computer programming.
Biology is a fascinating field. It wouldn't be wrong to say that it is the highest form of technology! Who knows, one day we may even discover that brain and intelligence are a result of a phenomenon which involves very tiny things interacting at light speeds - relativistic phenomena in the quantum domain!

Ok ok, this flight of fancy is going too high, let's land it ;). No, I am not in the field of biology. I am a mere engineer, whose only remote authority over the subject is having scored equally well in Maths and Biology subjects in 12th Science class, after which I needed to choose between one of the the two. There are lessons from 12th Bio class that are forever sharp in my head (at least until some biological calamity takes over it :P). And out of interest, I like to read up stuff on the internet and in popular magazines.
Combining these, I think there is a strong analogy between cell divisions and iterative loops (FOR, WHILE, etc) in computer programs. So today...yes you guessed it...I am going to tell you why I think so! 

An iterative loop has a code within it. Cell has genetic code within it. When an iteration is running, the code executes. When the cell is alive, the genetic code executes. When one iteration is completed, a new iteration may start, or the iterative loop may terminate. Similarly, when a cell is done with its current life it may either divide (comparable to a new iteration of the computer code loop) or it may simply die (loop terminated).

To extend the analogy further, the termination of iterative loop in a computer is decided by a counter, or a condition, or both. Typically, a counter is increased or decreased once per loop iteration.  It is also checked before the next iteration. If it reaches a set value, the loop is terminated. Scientists  have found something in living cells which is very similar! At the ends of the cell's code, there is something called telomeres. They are like as the ends of a shoelace, that prevent DNA from unraveling (and from fusing with another DNA sequence). When the cell divides by a process called mitosis (there is another called meiosis which is different, but we will not go into that), its genetic code or DNA duplicates and one copy goes to the each new baby cell. But the telomeres at end of the two new DNA copies are shorter than in the original one. One may think of it as if the available telomere ends gets divided between the two new copies of the DNA (Though this isn't scientifically very accurate, as far as I understand). As the cell goes on dividing, generation to generation, the telomere length reduces, just like a down-counter in iterative loop of computers. When the telomeres get too short to be able to reliably hold ends of the DNA together, it is as if the critical or check value of iterative loop is reached. The cell dies instead of dividing. The loop terminates instead of going for another iteration. The cell reaching a stage where it can no longer divide due to limitation of telomere length is called cellular senescence (which in simple words, translates to 'growing old')

However that is not necessarily the only way iterative loops terminates in a program. We could have additional condition checks before re-entering the loop. And sometimes we can even abruptly exit the loop when some error condition is reached in the body of its code. Similarly reduction of telomere below stable length is not the only way in which cells die. Without even going to complex scenarios, we can all agree that for normal aerobic (oxygen breathing) cells, cell will die if condition 'Oxygen available?' evaluates to 'No'. So yes, our analogy does still hold strong!

Pretty cool similarities so far, isn't it? But there is even more! When you are inside the body of an iterative loop in a computer program, most languages let you to write some code inside the loop which modifies the very counter that controls the loops. If your controlling counter is a decreasing counter, you could choose to increase it somewhere in the code, so that you can have more iterations that originally set. Similarly, cells have genetic code which enables them to increase the lengths of the telomeres, which we saw earlier are very much like counters for iterative cell divisions. Particular genes of the DNA produce an enzyme called telomerase, and this enzyme increases the length of telomeres at the end of cell's DNA. This enables the cell to divide more times, just like more iterations happen in a computer code if you increase the loop counter from within the loop's code!

Now, if you are familiar with computer programming, you might be tempted to ask, what about infinite loops? Is there a parallel for cells? Yes indeed there is! In many lower unicellular organisms, cell division itself is the reproduction of the organism so cell division must be possible over infinite generations, for survival of the species. Such cells celebrate lavish telomerase parties from time to time, at the right times, to keep extend the telomeres between cell divisions. Thus an infinite loop is achieved where the control variable (analogy for the telomere length) is decreased in between one loop iteration to the next (at cell division), but is again increased by suitable amount within the body of the loop's code block!  Note that bacteria don't fall in this category. They have circular DNA, which does not have end points and hence does not have telomeres. So I'd say bacterial reproduction is like a true infinite loop by comparison, which doesn't have any control variable at all! Just a condition that always says "Go ahead to the next iteration buddy!")

Lower unicellular organisms are fine you might say, but what about higher organisms? What about us? Well, we have got both kinds of cells we saw above. 'Finte loop' kind, as well as 'infinite loop' kind. In fact stem cells in the embryo have plentiful of the delicious telomerase booze flowing! Those guys know how to party! In fact they can work and form the whole human baby precisely because of the plentiful telomerase! You should learn the 'Party hard and work hard' mantra from these guys ;). So we can say the embryonic stem cells are the 'immortal' kind or infinite loop kind that keep producing more and more telomerase, elongating the telomeres, never dying for a silly reason like "Oops! We ran out of telomere!" However as a baby develops and grows, the party mood mellows down. The various kinds of body cells (somatic cells) that the stem cells differentiate into are 'finite loop' or mortal kind. They do multiply, till their telomere length allows them, and there is some telomerase action at various stages, depending on cell types. But eventually after dividing and dividing they run out of telomere, undergo senescence (the 'growing old' of cells I mentioned earlier), and are no longer able to divide. This is typically the situation is various parts of the body of an old person and believed to be the primary and unescapable cause of death, no matter what a great lifestyle you have maintained throughout life. However it is not a grim and moribund tale right from the time embryonic stem cells are gone. A person has various kinds of 'adult stem cells' in various parts of the body. They have the telomerase activity going on, and divide into more stem cells as well as specialize into various normal body cells for tissue growth and repair. Some prominent examples include:
In bone marrow - There are various kinds here. Some produce continuous supply of various kinds of blood cells during life of a person, Some produce cells that line the blood vessels of person, and some kinds may even run off from the bone marrow and help maintain lungs, bones, teeth, cartilages and even that fat layer we all  hate to have ;)
In the breasts: Help the breast tissue grow during puberty as well as pregnancy.
In the intestine: They divide throughout life of the person and produce cells that line the small and large intestine.
Olfactory stem cells (In the part of nose responsible for smell) : Frankly I don't know what they are doing in there. Maybe because olfactory by its job description itself needs to interact a lot with the external environment, the cells need pretty regular replacement from wear? No article was very informative about this, but it seems like scientists have great hopes from olfactory stem cells for future research and therapy. For one, they show potential for differentiating into various kinds of body cells. Second they are easy to obtain, without invasive operation like other stem cell extractions need, and even from very old people who would primarily benefit from stem cell therapy for some tissue replacement. (Own stem cells are important, for body not to reject tissue from stem cell therapy)
In the brain: It is known that new neurons indeed grow in the brain, But there is some controversy whether this happens from neural stem cells which can go on dividing in lab condition, or from progenitor cells (that for from neural stem cells) which are capable specializing into types of brain cells, but only undergo finite divisions (unlike typical stem cells)
In the testes: They let the sperm cell production carry on throughout life. Final division that produces sperm is meiosis instead of the usual mitosis that takes place in other cells of the body, but let us not complicate things here. (Fun fact: In most cells of the body, telomere length reduces with age, but in the sperms produced, the telomere lenght goes on increasing as the man grows older! So it seems that when a guy has kids at older age, the child has advantage of longer telomeres. There exists a slight-counter view as well, which we will see later)

(Talking of sperms, I dug around the internet if similar telomere lengthening happens for eggs in females too. Couldn't find. Info welcome in comments! Also till recently females were believed to be born with all eggs they'll ever produce, with typically one egg released per cycle, and hence pretty feasible to manage without stem cells. Very recently they found some egg producing stem cells in ovaries too)

So from what we see, although most our cells are not capable of immortality through 'infinite loop' of never ending divisions, there are some brooks of 'life force' called stem cells which do keep dividing and help us alive and fight death for much longer than otherwise possible!

If you have been following closely, at this point you might want to revolt "HOW THE HECK is it fair that lowly unicellular organisms get to divide infinitely, while the so called advanced organisms, including us super advanced humans, are on such a cruel telomerase countdown to death, thoughout life?" Well, take it easy, nature/evolution is actually trying to help us! Yes, you heard that right, by killing our cells through telomere countdown, nature is trying to help us! Let us see how.

Let us say there is a simple little computer program. All it does is chime out current Greenwich Mean Time, every 5 mins, in a never ending infinite loop, and once every 6 months, it triggers another copy of itself to start running in the computer. Let's say nobody actually uses the time that these clock display. Let us say the copied/duplicated clocks also don't interfere with each other's workings anyways. No suppose some external mischief maker sets one of the clocks to Indian Standard Time instead of GMT and waits gleefully to see if things blow up or not. He gets totally disappointed! Since we said the clock programs are running pretty independently and are of no use to anyone either, it doesn't matter. The GMT clocks keep running and produce more GMT clocks every 6 months and the IST clocks keep running and produce more IST clocks each 6 months.

For single cell organisms, the situation is very similar to the above one. They just keep dividing infinitely. Each cell is a complete organism in itself and lives for itself. No other cell is functionally dependent on its existence in a direct way (We are not considering creatures that feed on these cells). Sometimes circumstances play as the mischief maker and the cell mutates, but it is no big deal. The other cells continue the old species, and this new mutated cell, if capable of surviving and dividing, can become a new species altogether! It does not blows up the whole setup. Of course sometimes these two species may become rivals competing in same environments for resources. But still mutation of one cell doesn't directly kill other original creatures. So nature allows the unicellular organisms to go on dividing infinitely, because although mutations are more likely at some point in unlimited series of cell divisions, they are not a problem!

But what about the complex multicellular organisms? If genetic code of some cell(s) mutates (most likely during cell division) in some organ of the body, the resultant cells may work in ways different than how they are supposed to.  Usually that cell will have odd surface composition and immune system will recognize and destroy it. But if those cells don't die or get destroyed for some reason, and grow more by dividing and eating into surrounding tissues, it results in cancer. So, the simple question is, how do we reduce the chance of such mutations? Very simple! Since the mutations happen and propagate through cell divisions, nature decided to simply restrict the number of successive cell divisions! So the big irony here is, nature wants us to DIE natural deaths by running out of cell divisions so that we don't DIE because of mutations that cause disruptions and cancers in the body! Funny huh?

And speaking as we are about telomeres and about cancer, we simply cannot move ahead without discussing the strong connection between the two. We said that cancer is caused by mutation of cell's genetic code. But then even if the cell has a very very badly behaving mutated code, it would die out after some generations of divisions due to telomere limit, wouldn't it? Well, here is the thing, most mutations that become cancers include mutations that enable strong telomerase activity. So the monstrous cancer cells keep producing telomerase, keep elongating their telomeres, become immortal in that sense. Thus they keep dividing and infiltrating the vital body tissues. This is why many cancer drugs target telomerase activity, not letting cancer cells to divide too much. However a small percent of cancer types are also found to have other telomere lengthening mechanisms, which are grouped under name Alternative Lengthening of Telomere (ALT). But long and short of it is, cancer cells are so fatal precisely because of the telomere lengthening, which in a healthy body cell would be 'life-giving force'! Another irony of life eh? Just like how we die of old age so that we do not die of cancer, as we saw earlier! Let me also bring out another, little irony. As cancer is likely a result of mutation during cell division, it is most likely in body areas which are rich in stem cells. The list of adult stem cells I touched above (which is not exhaustive) may ring a bell!

(P.S.: We saw earlier that as the male grows older, telomere length in the sperms increases). But since good telomerase length could keep normal as well as cancer cells dividing, there is a controversy whether the longer temolere length of sperms, as the male grows older is a boon or bane to the child born. Most opinions seem to be on the positive side. Let me give my own too (just an intuition, no scientific claims whatsoever!) I tend to think that just like the details of  computer code are ultimately serving a larger purpose, so do mechanisms of nature. If a male has a child at an older age, it means 1) The male survived till older age 2) Was still fertile at the older age. So maybe there is something really good about the male's genes, so nature has designed (through telomere elongation) to give these genes a better chance, a longer telomere countdown in the next generation! I would feel the same logic would have been neat in female eggs too, but like I said earlier, as far as my reading goes, telomere elongation is not seen in eggs as age increases :( . Also this does't mean that men should in general have children when older. While indeed the children will have longer telomeres, with increasing age, the sperm could have some mutations which were not present in the body cells of the father.(which we are assuming nature wants to promote, by giving longer telomeres as a reward for dealing with age well.). So yes, the child could have longer telomeres, but health complications from bad genes)

There, I am done explaining my basic understanding of cell division, its restriction by telomere lengths, the role of telomerase in extending telomerase length, and the connection of telomeres with long life as well as cancer. I have derived this from all sorts of sources read at different times, but now mostly in my head. The analogy of computer iterations is my own spin on it. I fact I started this post just to present that spin. But then biology is such a fascinating field that it naturally took over the starring role in the post :)

The more you read about this and think about this, the more fascinating it all seems. For example, scientists are already looking for ways to extend lifespan by forcing cells to produce more telomerase or supplying it to them. That is like controlling the counter of the iteration, like I explained. There is so much more to know, so much to tell. This can never end, because scientists are finding newer and newer things, and with a significant time lag, we are finding it out from them :). But still I must end. So let me end with some trivia:

-A number of companies are already trying to cash in on these discoveries. At a huge price, they attempt to tell you 'true biological age' by studying your DNA and telling you how much telomere you have left. This is not very meaningful though, because there seem to be many other factors, such as structure of the telomerase, which varies between people. For some structures, even lower lengths may be better than those of higher lengths of others.
-Females have an advantage over men in telomerase department. Estrogen tends to encourage production of telomerase. Perhaps that is one of the reasons women have longer life expectancy than men?
-While growing telomere length is mainly possible only if telomerase gets active, losing telomere length can happen through various damaging factors. Hence lifestyle and environment do indeed affect them.
-Childhood trauma & abuse, stress, trauma, long illness, etc can reduce telomere lengths at much faster rates than normal.
-Exercise & yoga  are believed to support longer telomeres as we age. This is by preventing telomere erosion as well as by initiating telomerase action, though exact mechanism is not well understood.
-Exceptions have been found to the idea that higher the age, lower the telomere length. e.g in a bird known as Leach's Storm Petrel, the telomere length is actually seen to increase as the bird ages! In some frigate bird varieties, the telomere reduction happens up to some age, but then it slows down significantly!

Well, that's it. It is high time I end this. A post with so many scientific tidbits should ideally have a list of references I know. But I have been writing this since a few weeks now, initially only from memory of what I have read, and then googling for fact checking, and then including some other stuff too that I learnt from that. Frankly I have not kept track of the pages I visited. It was wikipedia, some journal abstracts, some science websites, etc. But then I am not writing a PhD thesis or journal paper, so yeah I don't feel too bad about not having my references ready to quote either. But I believe I have remained factual to the best of my knowledge. Any corrections/controversies/discussions etc are most welcome in comments!

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