Immortality and Cancer

So what if we could just program our cells to be immortal?  after all, that little jellyfish I talked about earlier can manage it.  And they've managed to reverse aging in mice.  And if old age in cells leads to old age in people, then immortality in cells leads to...

Ah, be careful what you wish for.  There are already two kinds of immortal human cells I know of.  One is stem cells (and the jury is out on this, I believe).  Stem cells are cells that have not yet differentiated; have not yet found their purpose in life to see the world and be a retinal cell,  or perhaps help out a bit in the kidneys.  They are common in embryos.  Anyways, we're not here to talk about stem cells.

The other type of immortal cell is a cancer cell.  Cancer is a multifaceted disease of diabolical  sophistication, but all cancers rely on one thing:  a cell somewhere has being given the signal to perpetually divide. 

Most cells in your body don't reproduce, although all have the potential to.  Skin cells reproduce, as do red blood cells, and others.  But for the vast majority, part of the deal of living in a multicellular organism like people is ixnay on the cell division.

Normal human cells will divide about, I think, 50 times and then die of old age.  But not a cancer cell. They go on and on and on.

As a matter of fact one woman, let's call her Mrs. Tibbets, died of a particularly virulent form of cancer years ago.  Researchers were particularly interested in her cells, so they have kept her cell line going for decades in laboratories the world over.  In a way, you could say Mrs. Tibbets is still alive, as a 50 ton tumour dispersed throughout the globe.  Her DNA, albeit with a cancer mutation, is still alive in each of those cells.

So maybe this cell immortality ain't all it's cracked up to be. 

Cancer overcomes the "natural" aging limits on a cell, the genetic programming that leads to cell old age, or senescence.  A lot of things have to go wrong for you to get cancer.  First of all you have to get a mutation in your DNA which instructs the cell to just keep dividing over and over again.  Second of all, the cell's elaborate defence mechanisms that fix mutations or otherwise prevent rampant cell division have to be rendered inert.  And third of all, an obscure little enzyme called telomerase, active when you were an embryo and your cells were dividing like crazy, has to be manufactured by the cell again.  If I understand the theory correctly, anyway.

Telomers are little caps on the end of your chromosomes (DNA villages, if you will) that act as an internal clock for your cell.  Each time the cell divides a little bit is shaved off the cap, and when it is gone your chromosomes start sticking to everything and to each other, all hell breaks loose and the cell dies.  Telomerase creates more telomers, so that the cell can keep dividing without limit. 

A mutation may cause your cell to get, or to think that it is getting, growth signals to divide.  What is supposed to happen is that, when excessive or unscheduled cell reproduction is detected, tumour suppressing proteins like p53, the sentinel, shunt the cell to premature senescence and put a right stop to that.  But if something goes wrong with the gene that make p53 then that defence may be rendered ineffective.  And not just p53; in cancer a host of tumour suppressing genes must be stopped.  Even if the mutation is allowed to drive cell growth, there is still the cell clock—telomers—that will kill the cell after a certain amount of cell divisions.  Unless another mutation has instructed the cell, after all these years, to start manufacturing telomerase again.

Slim chance right?  Well, as stated last time, your average cell DNA probably gets hit by various things that can cause mutations tens of thousands of times a day.  You've got somewhere between ten and a hundred trillion cells.  Do the math.

So, having defeated this elaborate mechanism the cell is free to divide at will which it does.  It has become immortal.  Theoretically anyway.  In reality, of course, it winds up killing the host organism and dies with it.  (Except for Mrs. Tibbetts's tumour, which is still going strong.)

The interesting thing is that this p53 tumour-suppressing gene is believed to have a directing role in cell old age.  When p53 suspects something is wrong it pushes the cell towards old age, as a defence against out-of-control cell division.  From an evolutionary perspective, this is understandable—you don't want sub-standard cells dividing.  Just like old people, old cells have a hard time being active and reproducing.  Over time your DNA accumulate mutations—ones that may not necessarily cause cancer, but mutations nonetheless—and it's thought that perhaps these tumour-suppressing proteins like p53 initiate the old age program.  They prevent the cell from dividing, and perhaps (for cells that don't reproduce) from even from repairing itself properly.  So the cells don't work as well as they should and the overall affect on the body is old age.

From this point of view, aging itself can be seen as a defence mechanism against early cancer.  The tumour-suppression genes are great early on at preventing cancer.  Without them cancer would be very much more prevalent in younger people than it is.  But as the DNA accumulates random damage over time, the tumour-suppessing proteins detect this and institute the genetic senescence program.

Given that aging and cancer may be competing interests, it looks like my hopes of an immortality pill are slim.  I might get cellular immortality, but I'd be ripped apart by tumours soon after.

On the other hand, this is all theory.  Some researchers think that there are programmed "senescence effector" genes that actively initiate aging upon reproductive maturity.  Maybe it's just turning those cells off. 

As for immortality, dammit, if a jellyfish can do it, why can't I?


Incidentally, I should give a nod to William R. Clark's excellent text A Means to an End: The Biological Basis of Aging and Death, which was my primarily resource for this series.

Aging Part 2: How People Rust

The more you complain, the longer God lets you live.

     —Old Proverb

This is the middle part of three posts on the science of aging and immortality. Like most middle parts, it's really boring.  If I were you I wouldn’t even waste my time reading it.

Still here?  More fool you.

Back in the early days, about three billion years ago or so, photosynthesis was all the rage.  This is where plant cells would create energy by converting carbon dioxide in the atmosphere into oxygen.  Oxygen, previously  trace element, started to accumulate up to its present concentration of just under 20%.  So the theory goes anyway.

Now most people get a nice feeling when they think about oxygen, probably in no small part due to the fact that they'd be dead in a few minutes without it.  But oxygen is actually an extremely corrosive substance.  Fire, for example, is simply a runaway oxidation reaction (organic carbon à carbon dioxide).  Rust—estimated to cost the economy US$2.2 trillion or 3% of the global GDP—is also oxidation.  Spoiled food—yup, oxygen.

Vigorous oxidation reaction.

 Eukaryotes (remember, cells with a nucleus are called eukaryotes; and cells without, like bacteria, are prokaryotes) didn't much care for this corrosive substance accumulating in the atmosphere.  So they made a deal with some little bacteria.  The bacteria were like, "Hey dude, let me  live here in your big cozy cell and I'll deal with that oxygen problem you got,  plus I'll pay rent in energy."  And the eukaryote cell was like "Awesome!  Stay as long as you like."  And the bacteria did. For the last few billion years.

Those bacteria, called mitochondria, are still there, in every single cell of the trillions of cells in your body. Not just human bodies, but every cell in a dog's body and every cell in every flea that lives on the dog.  They are not part of "you"; they contain their own DNA.  (Actually, because mitochondria DNA passes on to the child from the mother only, apparently we can trace every human alive back to one woman—the Mitochondrial Eve—who lived about 200,000 years ago.  But that's a blog post for another day.)

The mitochondria are the furnaces of the cell, burning (oxidizing) food to create energy.  But like all furnaces, there's issue with leakage and problems with stuff that doesn’t get completely burned.  Sometimes they form highly reactive chemical intermediaries called free radicals, which, like political radicals, are unstable and wander about basically looking to start trouble.  These radicals can mutate the DNA either the mitochondria or, uncommonly, of the parent cell itself ("your" DNA).  It's believed the DNA mutations caused by this (called oxidative stress) contribute to cell senescence (old age).  In a way, we rust.

Problem is, it doesn't explain why dogs, who basically share 80% of our DNA, burn through seven years for every one we do.  Or why a flea, which still has about 60% shared DNA with humans (scary, isn't it?) die within weeks.  It doesn't make much sense, given the similar cell mechanics and biology, that humans live a hundred times longer than a flea, or thirty times longer than mice, or seven times as long as a dog.  With such similar cell genetic characteristics, why don’t all species have similar wear and tear and therefore similar life spans?

Nobody really knows why as far as I can tell.  A prevailing theory is that, because humans reproduce when we are relatively old compared to, say, fruit flies, and because we spend a long time rearing our young, our cells have developed more complicated mechanisms to prevent or repair cell mutations caused by oxidative stress, ultraviolet light, radiation, viruses and just-plain intracellular cock-ups where one of the proteins screwed up on the Friday afternoon shift and created a mutant. 

Evolution would breed out mutations that kill us before we reproduce (that gene line would abruptly end), but mutations that kill us after we reproduce will not be "bred out" by evolution?  Let's say you're a car.  It's not like your genes are taking it in for preventive maintenance to get a good resale value.  No, if you're a car, your genes are like "Get this thing to Vegas, then who gives a rat's ass what happens to it."

Your body, according to your genes.

When you are young, your cells are good at dealing with mutations.  One protein, for example, p53, is a real Horatius at the Bridge against mutant-causing agents.  If it detects damage to the DNA it slows down the cell cycle until it can be repaired.  If the damage to the DNA is severe, it even initiates cell suicide.  Later in life, as cell mutations accumulate over time, and poor old p53 is a lot busier and starts to build up in the cell, inhibiting the cell cycle and shunting the cell to senescence, or old age.

p53 protein (white), a guardian of the cell, attached to DNA (green and blue)

So the courageous "Thou Shall Not Pass!" p53 protein and others like it, that protect the DNA early on eventually lead to cell senescence and death.  So the theory goes, anyway.

Interestingly, there is one way to lengthen life span significantly—at last in lab animals.  Calorific restriction.  Animals that get all the nutrition they need, but have their calorie intake reduced by about 40% live 50 to 80% longer than normal, and live active lives.  Calorie restricted primates have a slightly lower core temperature than others, leading to speculation that a less active metabolism slows down the bodies aging mechanisms.  So if you eat nothing but a little bit of green beans and tofu every day, you may indeed live significantly longer.  Even if you don't, it'll certainly seem that way.

So, cell senescence may be due to an intracellular "autoimmune response," if you will, as a result of DNA mutations that naturally accumulate over time.  Considering that your average DNA gets hit by mutagens tens of thousands times a day, and multiply that by a hundred trillion cells or so in your body, you can see how they'd add up.  But eventually the mechanism designed to repair such damage shunts the cell to a senescent state.  What if there were a way to fool the cell into thinking it was still young?  What if you could make the cell immortal?

Next up:  The exciting finale—Immortality and Cancer

Sex and Death (and Immortal Jellyfish and Mind Control Parasites)

Everybody has got to die, but I have always believed an exception would be made in my case.

     —writer William Saroyan's last words

It's my birthday today.  Yay.  I'm 47.  Nothing really special about 47.  It's prime, and I won't be a prime number again until I'm 53.  That's about it.  Now that I'm getting on a bit I've become suddenly intensely interested in aging. 

We all get old.  We all die.  Now dying sucks for two reasons.  First of all, it's painful. And second of all, at least as far as science goes (which isn’t that far),  when you die you never come back again.  The molecules of which you were presently comprised are still lying there, but you, the ghost in the machine, are forever gone from this time and place.

When you examine the biological basis of aging, as we will over the course of  the next blog post or two, one of the things that you will find striking is the close relationship of aging to cancer.  It's in vogue now to be really mad at cancer.   To rail at it.  To hate it.  To treat it as an enemy.  You don't "have" cancer; you "battle" cancer.  You see t-shirts emblazoned with "F%$K CANCER."

You tell 'em, Sarah!

And yet we don't have the same attitude about aging.  Heck, we even tut-tut those who refuse to "grow old gracefully."  Nobody gets mad that they are dying of old age, even though, like cancer, it is slow, painful and undignified; and unlike cancer, it is not survivable. 

Not me.  Getting old pisses me off, frankly. 

Old age has been around a long time.  But not, according to many faiths, forever.  Adam and Eve were immortal until they ate the forbidden fruit.  Then God made them mortal.  Of course, Christians—as well as most religions I can think of actually—believe in the immortality of the soul, but that's another topic. I'm taking strictly about immortality of the flesh here.

A quick review of many faiths reveals that most gods are immortal, and the condition of being human was to be somewhere between the animals and the gods—where the rising ape meets the falling angel, to steal Terry Pratchett's phrase.  Many faiths believed that humans descended from gods and the act of becoming mortal was the act of becoming human.  That is, mortality was the defining feature of humans.

But we'll be discussing it from a Darwinian perspective, because that's the creation myth I happen to understand best, as a scientist. 

We don't have to get old and die, from a physics perspective.  We wouldn't be breaking an laws of conservation or thermodynamics by staying alive.  So why do we age?  Who decided that was a good idea?

Recently there was an interesting article in the Guardian: "Scientists Reverse Aging in Mice."  Actually, the title was  a little deceptive.  (The media? Deceptive?  Noooo.)  It's like a couple of years ago they announced that they had achieved teleportation.  I thought "Wow! That's news."  Except that they'd only teleported a subatomic particle.  Well, that should be useful if I want to send my son a frickin' proton for his birthday.

Anyways, the mice in this case weren't real mice. They were Frankenmice.  They were mice genetically engineered to age quickly, and then they fixed the genes that they had deliberately screwed up to start with.  It was still pretty impressive though.  They didn't just slow down again in old decrepit mice.  They reversed it.  These old fogie mice were growing new neurons, becoming active again and boning like crazy, excuse my French.

In other news, scientists recently discovered something about this unassuming little fellow.

Turritopsis nutricula:  the immortal jellyfish

 It's a jellyfish about as big as the head of a thumbtack.  Intensely uninteresting, you would think.  But here's the thing about Turritopsis nutricula.  It's potentially immortal.

Actually what it can do is revert to a juvenile state in times of stress.  Now when I told my buddy Mike this at the pub his response was "So what?  So can I."  You can't argue with that guy.  When times are tough for this little jellyfish, it can go back to being a polyp again when life was simple and it didn't have a care.   Wow.

Now before we get further into this, we have to make sure you understand how the whole Darwin thing works.  Old people are invisible to evolution.  If you die, before you procreate, your genes die with you and that's the end of that.  But if you manage to procreate, then your genes carry the torch for another round. 

So, if you have a gene in your DNA that creates a protein that convinces your brain that yelling, waving your arms and rolling around in gravy whenever you see a tiger is a good idea, chances are that particular gene—along with the body unfortunate enough to house that gene—is not going to last long.

(Don't laugh.  Turns out that there is a feline intestinal parasite that does just this.  If it finds itself unfortunately crapped out by the cat, it may end up being ingested by, say, a mouse.  The parasite wants to be back in a cat's digestive tract so what does it do?  That's right. It resides in the mouse's brain and convinces the mouse to engage in risky behavior to increase its chances of getting eaten by a cat.  It makes fear sexy for the mouse.  I'm not making this up.  Not only that, but it there is evidence that humans infected with this parasite also "involuntarily" engage in risky behavior.  Note to self:  future blog post on alien mind control.)

Anyways, where was I?  Oh yes, Darwin.  So, any genetic disease that effects you after you've finished all your procreating—like Alzheimer's Disease, for instance— has already been passed on to your progeny.  It will not be weeded out by evolution.  The whole basis of the theory of evolution is that you—the human being reading this—are just a particularly elaborate life support system for you genes.  That's it.  You have no other purpose except to propagate your immortal genes.  The whole thinking, being, feeling, appreciating art, striving for the divine is a side effect. An emergent property of a complex system designed to provide a nice place for your genes to hang out prior to propagation.

For the most part, your body does what it can to stay alive, so that you can procreate.  But after you're done that, and you've adequately cared for juvenile life forms that contain you genes (i.e. children), there's really no reason for your genes to go to all the trouble of keeping you around.  So it's probably no coincidence that aging really sets in with a vengeance as soon as your prime reproductive years are behind. It's also probably not a coincidence that the life spans of various animals correlate with the ages at which they reproduce and the time they spend rearing their young.  If you reproduce young, you die young.  The life spans of fruit flies were significantly extended by creating a colony that reproduced when they were older.  For animals, bivalve molluscs live the longest, flowed by tortoises.  Humans place third and elephants are behind us.

Bacteria are immortal.  Give 'em a nice place to live and they'll go on reproducing forever.  Bacteria reproduce by binary fission.  They basically clone themselves by splitting into two.  Human cells—actually all animal, plant and microorganism cells—are different.  They’re a lot bigger, to start with.  And they have a nucleus, and a double helix DNA.  In scientific terms bacteria are prokaryotes, and cells with a nucleus are eukaryotes.

The paramecium is a eukaryote.  It is a single-celled organism with a nucleus, about a million times bigger than your average bacterium.  The paramecium can reproduce by fission—or it can have sex (or what passes for sex for a paramecium).  

Parameiums getting it on.  Does this count as porn?

What's interesting is that, on the evolutionary ladder, the paramecium is about the earliest life form that (a) has sex, and (b) ages.  It seems that cell senescence (or aging) arrived the same time sex did.  There's strong evidence the two are related.  Indeed, if you are unfortuante enough to be a male praying mantis, the relationship is more than theoretical, since the female tears of the head of the male and eats him after sex.  Not much better if you're a male anglerfish, either.

 

It's interesting: Eve was tempted by the serpent to eat the forbidden fruit.  After they had eaten the apple, Adam and Eve became ashamed that they were naked, God made them mortal, cast them forth from Eden, and then they begat Cain.  So the idea that sex and death are intimately related and came about at the same time, something we theorized only a few decades ago, is echoed in the oldest writings of humanity.

Next time: Are we programmed to die?