Of Spelling Mistakes and Cancers…

In these pages I have oft referred to cancers as diseases of genes and mutations. That is, mistakes or mutations that develop or accumulate in our DNA can sometimes lead to the onset and development of diseases like cancer.

Does that mean that cancer is inherited?

Actually not for the most part, although it is true that in a limited number of cases mutations that can cause cancers may actually be inherited from one or other of our parents. These are so-called “germ-line” mutations that are passed on from parent to child, at the time of conception. Such mutations are thus found in every single cell of the affected person’s body and may then be passed on to subsequent generations through either sperm or egg cells. Generally speaking, these types of body-wide mutations are more likely to create a condition that predisposes one to cancer development in the future, i.e., may aid and abet in the development of a cancer, as opposed to outright causing the cancer directly.

The more likely route to cancers by far is through a different mechanism, called somatic cell mutation. Somatic mutations are mutations that happen in any other cell type in the body OTHER than the sperm or egg (the so-called germ cells). As such these mutations are more what we might call “sporadic” in that they arise unexpectedly and they show up only in the cell in which they first arose, PLUS any daughter cells that may have been produced by the normal activity of cell division. For example, if a mutation arose in a single skin cell due to UV radiation damage, a copy of that mutation would be passed to other skin cells that arise when the originally mutated cell divides, but new skin cells that arise from the division of normal healthy skin cells would not have the mutation. So you can see that you will end up with two distinct populations of cells – a small population of abnormal daughter cells that are descended from the parent that had developed the mutation in the first place, and a much larger population of perfectly normal cells that descended from normal parent cells in the usual way. Now, if that mutation in the small population of cells ended up creating a melanoma (skin cancer), for example, sequencing of the DNA from the tumour cells themselves might show the mutation(s), whereas all other healthy skin cells from the very same patient would not have the mutation(s).

Where do these somatic mutations come from?

That is the million-dollar question that is at the heart of all cancer prevention. That is, if you can avoid the development of cancer-causing mutations in the first place, then you avoid the cancers! So, by not smoking or using tobacco products, by not breathing in coal dust or asbestos fibres or other workplace hazards, by not staying out in the sun too long unprotected and/or using tanning beds, by eating a balanced, healthy diet and getting physical exercise etc., you can reduce your risks of generating mutations in your body cells that might eventually lead to cancer.

Unfortunately, no matter how diligent and careful one is to avoid exposure to these so called “carcinogens” – those agents that we know can create mutations in human cells and therefore might lead to cancers – or to maximize a health-promoting lifestyle, I am of the belief that we will NEVER really be able to prevent cancers altogether. Does this mean we shouldn’t each do everything we can to reduce our own risks as much as possible? Of course not. But if our dream is the overall eradication of cancers, like we can dream of with some infectious diseases, it is just not going to happen.

For one, we are unlikely to ever understand and identify ALL agents that might cause mutations and lead to development of cancers.

But in the main, the reason we will never eradicate cancer outright is that, as one of my colleagues quipped one day, “The number one cause of cancer is… breathing”. By this, he did not mean breathing in carcinogens; he meant that as long as we are alive and on this earth, there are natural processes ongoing in our bodies that can (and do) create mutations that can (and might) lead to development of cancers. And short of “stopping breathing” – NOT a very good alternative! – there is little we can do about that….

This is why cancer is often thought of as a disease of aging. The longer we live, the more prone we are to developing cancers in general. That is why cancer statistics are usually “age adjusted” as I described in an earlier post. 

In order to better understand why the very processes necessary for sustaining life are also constantly putting us at “risk” we need to examine some of the most fundamental mechanisms underlying molecular biology, and especially how our DNA makes copies of itself every time a cell divides, since errors in this process that are the fodder for genetic mutations.

helix2The schematic of a tiny piece of a DNA molecule depicted at the left is one everyone is familiar with. DNA molecules are very long helical, or spiral, “ladders” comprised of a specific sequence of 4 building blocks called nucleotides, which we abbreviate for simplicity as “A”, “T”, “G” and “C”. The wonderful feature of this ladder type sequence is that each rung in the helix is normally comprised of either an A-T pair or a G-C pair. In other words, A and T always pair up together and G and C always pair up together. Whenever you have an “A” on one side of the ladder, you will have a “T” on the other. If you have a “C” on one side of the rung, it will always pair with a “G” on the other.

What this means is that if you peel the helix apart by snipping it right down the middle and breaking each pair, you have actually preserved the information for making the ladder intact again.

If you look at the diagram below, you will see this depicted diagrammatically. As the strands of DNA are separated right down the middle, the strict pairing rules mean that each strand is now a TEMPLATE for its complementary strand.

 

DNA replication (from visionlearning)

This critical complementarity is the basis for the replication, or copying, of every single DNA molecule each and every time a cell has to divide into two new cells. The strands of the DNA molecule separate, and each strand becomes a template to recreate the information in the original duplex again. Only now there are TWO identical duplexes, one for each daughter cell!

Below, courtesy of the DNA Learning Center, is an incredible animation that shows this process much better than mere words or diagrams:

 

Why and how is all of this important for cancer? Because in the language of DNA molecules, exact spelling counts, but the cell machinery, like all of us, sometimes makes a spelling mistake….

Let’s go back and just contemplate the sheer magnitude of the task of making these DNA copies.

You may recall an earlier post where I posed a thought experiment to you: I asked how long it would take for any one of us to read out our entire DNA sequence from the tip of chromosome 1 to the end of chromosome 23. Even if you read them out at the rate of 5 ladder rungs per second, 8 hours a day, 5 days a week, 50 week a year, it would take you about 84 years (!) to read your whole DNA sequence. That’s because our genomes are about 3 BILLION ladder rungs. That is a very big number Winking smile

Another very big number is the number of cells that make up a normal human being. Since no one can actually count them we have estimates that range from about 10 TRILLION to perhaps as many as 100 TRILLION cells in each human body! Some of these cells divide all our lives – cells like those found in our guts and digestive systems, or cells in our blood stream, or our skin cells – old cells that are constantly being replenished with new ones. Other cell types in our body divide much less frequently, if at all, in adults. Cells in your heart, or your spinal cord, for example, do not usually divide and replenish (which is why spinal injuries or heart attacks can cause irreparable damage…).

However, it has been estimated that in one’s (normal) lifetime as may as perhaps 10,000 TRILLION cell divisions occur from among all those cell types that do divide.

Imagine that – 10,000 Trillion cell divisions, and each one of those has to be preceded by a DNA copy process that sees about 6 Billion base pairs of DNA copied (when you take both strands of DNA into account) and that all has to be done with absolute precision

The numbers (and demands!) are nothing short of staggering…

Let’s put that in a bit of real-world perspective. I fancy myself to be a pretty decent speller. I have a large vocabulary and I know how to spell very well. I’m not such a great typist, mind you, but spelling is a forte of mine Smile.  Add in computer spell-checkers and the like and we have the makings of a pretty accurate writer and speller.

If I said that my typo or error rate was, say, 1 in a thousand, I bet you would all think that was pretty good, right?

Well, if the DNA copy machinery in the cell was that accurate – 999 correct out of each 1000 bases copied, that would mean that every single cell division would result in about 6 MILLION MISTAKES in each and every cell that divided! Clearly we would not live long if that was the best our cell machinery could muster.

What if the error rate was a paltry 1 in a million? I would love a spell checker like that, but in the DNA world that would still mean that each and every cell division could yield as many as 6,000 mistakes!!   Still nowhere near good enough…

In fact, the actual cellular machinery, when working at full tilt, has a series of intricate molecular proofreaders, editors, checks and balances and actually achieves an almost unbelievable average accuracy rate of perhaps as few as 1 mistake in every 10 BILLION transactions (I have seen estimates range from 1/billion to 1/100 billion).

But even at that unbelievably low error rate, because of the sheer numbers of DNA building block that have to be copied each and every time a cell divides, that means that a mistake still gets through the spell checkers periodically. Perhaps 1 mistake in each 1-10 cell divisions. As a relative number that is so miniscule as to be laughable, but in absolute numbers, especially when accumulated over a lifetime, that is unfortunately still a LOT of mistakes…

The really good news is that most of those mistakes are of little or no consequence – a big yawn – they occur in DNA stretches that simply aren’t important. We don’t know they are there, and frankly we don’t care. They don’t affect our lives and the ignorance of them is indeed “bliss”.

But once in a while, an uncorrected mistake gets made that really does have a negative consequence. Once in a while a spelling mistake happens that changes one critical word into something that no longer makes sense, a mistake that changes the meticulously orchestrated vocabulary of the cell. And the longer we live, the more and more likely it is that this sheer law of averages sooner or later catches up with us, and one or more of these undetected and uncorrected mutations leads to the start of the cellular disregulation we know as cancer.

Now you can begin to understand the adages that “cancer is a disease of genes and mutations” and “cancer is a disease of aging”.

As always, however, there is much more to the story than I have been able to simply show here. More to come Smile

     
 
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Comments

Of Spelling Mistakes and Cancers… — 3 Comments

  1. Hi. I got a question for you.
    If cancer is a problem in the replication of cells, how can it spread to other types of cells. I thought that cells replicated the same cells types? As a skin cell would produce skin cells?

  2. It is a pretty good overview for laymen or someone who is generally interested in cancer. What are the approaches we are using to detect cancer variants at this point?

  3. As a layman, I greatly appreciate the clarity of your writing. Thanks for bringing such a complicated topic closer to earth.