WHY WE HAVE TO DIE AND THE RISE OF THE MUTANTS

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Two neuroscientists, Bertie and Arnold walk into a bar and before they order their drinks, Arnold says to Bertie – “I bet I could ask you a question that would leave you really stumped”.  Bertie answered: “if it is a legitimate question, I could give it a go, but as you know, even a fool can ask a question that a wise man cannot answer”.  Arnold replied – “well, this is not such a foolish question, I just want to know why we have to die and if we can fix that?”.  Bertie responded: “well your cells grow by dividing, they keep dividing until they have errors, then they become cancerous or decay in function, or stop dividing, and then you die”.  Arnold said – “well, let us explore just a mere fraction of what we know and see if you are right”.

Bertie continued: “What really enthralls me is that some of the central characters in this story to find a neuroscientific basis as to why we have to die have luxuriant, exotic, and imaginative names.  Have you heard of Indy?”  Arnold replied: “now you are toying with me. He is a character in that film series called Indiana Jones, and he portended to be immortal”. “Wrong” exclaimed Bertie – “Actually, INDY is an acronym that means I’m Not Dead Yet, which… wait for it, hails from Monty Python and the Holy Grail.  So, there is a movie element to this story”.  “Tell me more” said Arnold – “who’s not dead yet?”.

Bertie settled into his seat and started to speak in hushed tones as if he was conveying a dark secret – “Well, in 2009, two really smart scientists at Brown University (http://www.pnas.org/content/106/7/2277.abstract) discovered that reducing the activity (scientists call it expression) of the INDY gene extended greatly the lifespan of the fruit fly, which goes by the captivating and rather elegant name of Drosophila Melanogaster. Now let me tell you something about Drosophila Melanogaster that would be useful in a scientific trivial pursuit contest. Yes, everyone knows they came from Equatorial Guinea and have been spread to almost everywhere in the world by human activity. But did you know, that they were first described in 1830 by Johann Wilhem Meigen, who got his doctorate at the age of 83 years, just a few weeks before he died – talk about perseverance and life-long education!?” “Now you are showing off” said Arnold – “what about these fruit flies”.  Bertie shrugged of his smug grin. He liked knowing silly facts that seemed to amuse him. He continued – “These mutant fruit flies lived more than twice as long as non-mutant fruit flies.  It would seem that this life-prolonging effect was due to the reduction of free radicals and oxidative damage in the energy producing cells, the mitochondria.  If you like, the effect of the mutation was to act as an anti-oxidant right inside the cell itself to decrease aging”.  “Ahem” said Arnold – “perhaps that is why people keep chugging down all these drinks that say they are loaded with anti-oxidants”.  Bertie frowned and scolded – “before you rush out to buy a whole bunch of anti-oxidants, there really is no solid evidence that consuming anti-oxidants will extend your life or slow down your ageing process as a human. We are not fruit flies. Nor does rubbing anti-ageing creams into your skin that contain anti-oxidants, even the most exorbitant ones, make much difference to your ageing process. It really is not as simple as that! Wish it was”.   Arnold interjected – “So, this process of ageing and dying has something to do with your genes.  We all know genes make proteins, and these proteins are essential for many functions of the cell. Do proteins themselves play a part in ageing and dying?”

“You are a clever man” said Bertie. He continued – “As you know, genes express themselves (i.e., show their activity) through the production of proteins that are, as you said, essential for many functions of cells including communication.   Cells have to put all these proteins somewhere so they fold these proteins tightly. Think of it like folding your laundry so that there is more space in the laundry room. That way, it is neat and tidy, and you do not hurt yourself bumping into things.  When these proteins are folded wrongly they create a “mess” and take up more space, and do not work well.  Cells have smart ways to clean up this “mess”, by trying to refold them, and if that does not work, destroy them, before they cause even more terminal damage to the cell.  This “mess” caused by misfolded proteins is, therefore, linked with ageing and cell death.  So, to sum up, ageing is inextricably linked to dying.  Arnold interjected “We really are dying all the time, even though we think of ourselves as being alive, and as we grow old, more of us is dying.  Dying is a long process for our cells…quite sad really”.

“Ah” said Bertie, “some other smart chaps have given us some hope”.  Bertie continued: “In 2011, Gordon Lithgow and colleagues (Nature doi: 10.1038/nature09873) showed in ageing worms dying from this “mess” of misfolded proteins that if they were fed the yellow dye, thioflavin, their lives were extended by up to 60% to 70% because this helped send an alarm bell to the cell to deploy its repair mechanisms to clean up the “mess”. I suppose, “cleanliness is truly close to godliness”. So, to sum, cleaning up the “mess” of misfolded proteins in a cell prolongs the life of worms. We really do know quite a bit about prolonging the life of fruit flies and worms!  See also: Ewen Calloway in: http://www.nature.com/news/2011/110330/full/news.2011.193.html and Andreas Keller in: http://vosshall.rockefeller.edu/reprints/KellerCB07.pdf.

“All right” said Arnold, “can we order our drinks because all this talk of fruit flies and worms has not done much for my appetite?” Bertie responded: “Just coconut water for me, don’t drink much alcohol – just a bit too acidic”. “Suit yourself” said Arnold, “I know what I’m having”.  Arnold continued: “Well, do we have any clues in humans?  I presume there is a lot of work going on to see if we can turn genes on and off that can stop us ageing and dying?”.

Bertie smiled sardonically and said: “I have another mutant story for you, and this one is even more grim and depressing.  The entire human race is dying and will one day become extinct. Our genes through the generations are mutating at an incredible rate, and at some point, our DNA will degrade to the point where we will not be able to have children and we will die out.  Have you not noticed that the number of gene mediated illness and cancers is rising?  Cancer Centers keep getting bigger (as they should), and if we do not find an answer, that will be it for all of us. In short, we are all programmed to die…even though it will just take a very long time” Arnold started to cough and splutter, he did not much like this doom and gloom discussion.  He had planned a quiet and relaxing night out, and now he was getting a bit tense.  “OK Bertie, forget about the human race, how can we tell when we are going to die?” asked Arnold.  “Well”, started Bertie, “that is truly complex but I can give you a few interesting notes.  You will remember our DNA is wound around our chromosomes and at their very ends, they have this stranded tip that looks a bit like a plastic tip and the end of a shoe lace that protects it called telomeres (discovered by the 2009 joint Nobel Laureates in physiology and medicine Elizabeth H. Blackburn, Carol W Greider, and Jack W. Szostak). When you are born, these telomeres are long, and as you grow older and your cells divide, they get shorter, and eventually they become so short that the cells die, and you die.  Telomeres do not cause ageing they simply register it. Let me tell you something that is really fascinating.  Child abuse and bullying shortens these telomeres.  So, not only can bullying cause all sorts of mental health problems in later life, it can actually shorten your life.  Bullies may be like murderers!”  “That a bit rough” replied Arnold.  He continued: “who would have thought all of that? And what about cancer killing you, surely that has a part to play? (see Joseph Stromberg in: http://www.smithsonianmag.com/science-nature/can-your-genes-predict-when-you-will-die-164511528/ ;  Michael Snyder and John Sanford in: http://thetruthwins.com/archives/the-human-race-is-dying-dna-degeneration-would-eventually-lead-to-the-total-extinction-of-humanity, and Adam Leith Gollner in: http://www.salon.com/2013/08/18/live_forever_can_science_deliver_immortality/.

Bertie looked hard at Arnold and broke into laughter. He then said “I am sure you have guessed that this is again another mutant story”.  Arnold could no longer help himself and quipped “Bertie, you seem to be the master of mutant stories”. And then their eyes met and they both burst out laughing.  Bertie continued: “I will be quick with this one because now we are really getting out of my expert area.  The name of this culprit is p53.  P53 (actually it should have been named p43.7 because its weight is a maximum of 43.7kDA) is a protein, that suppresses tumors. It is really like your defensive armor and shield against tumors because it wakes up (i.e. Activates) a whole army of helper genes to bring about a swarm of cell protection devices.  Cells do not like to die of cancer.  The p53 gene is located on chromosome 17”.  “There you go showing off again” said Arnold – “let’s just cut to the quick”.  Bertie wasn’t to be put off – “I will tell it simply.  If your p53 gene has just one copy, you develop a cancer (Li-Fraumeni syndrome), and if it is damaged by toxins, and or oxidative stress, the person is vulnerable to cancers. So, you would think that producing a lot of p53 would be a good thing.  Wrong again! It seems that an over-abundance of p53 actually can hasten cell death, which is called apoptosis!  So, too little or too much p53 will kill you so a good deal of research into cancer and its relation to ageing and death is all tied up in understanding more about the regulation of p53”.  Arnold shuffled in his seat and said – “I’m getting really tired and I need to get some sleep.  Is there any hope of immortality?” (see: https://en.wikipedia.org/wiki/TP53).
Bertie started to get up too and stretched his long legs as he did.  “Well, your genes seem to have the last laugh. Can you believe that even a few days after you die, some of them are just waking up in a vain attempt to save you? But for now, Arnold, there is no immortality in sight. And even if we could work all this out, it would likely not be forever.  Enjoy it while you can! Same time next week Arnold?” “You bet” Arnold replied.