In my last post, I described how tumours can become resistant to therapy by activating survival mechanisms, through a process known as Multidrug Resistance. I’m now going to talk about another way that therapy resistance can emerge, through the way that different tumour cell populations respond to therapy. And, specifically, how these responses can be explained by evolution. That’s right! Darwinian evolution!
Now, in order for me to explain how Darwinian evolution can be used to describe tumour responses and therapy resistance, I think it would help if you have an understanding of the basic concept. And while I’m sure that most people do understand the basic concepts behind Evolutionary Theory, I’m going to spend the rest of this post having a go at explaining it to those who don’t. I’ll then go on in the next post to relate it to cancer.
So. Here we go. Darwinian Evolution 101:
Evolutionary theory, as first described by Darwin and Wallace, explains how new species emerge. Evolution happens through what is known as Selective Pressure. This term used to describe the forces that shape how populations change over time after, for example, a change in the environment. So, basically, it could be said that Selective Pressure is just a fancy way of saying “Chances Of Staying Alive After Some Bad Shit Happens.”
Let me use an example to try and explain. Imagine that there is a very big plain with a river running through the middle. On one side of the river (the East side), there is a population of wildcats. On the other side (the West side), there is a population of field mice.
Now, these two species have never met. The river is so wide, that the cats have never been able to cross over to mouse side, and the mice have never crossed over to the cat side.
And so, for generation after ageneration, the cats and mice have lived on their own side of the plain (their own specific environment), without any idea that the other species is there. But then, the environment changes.
Some Bad Shit Happens.
One day, there is an earthquake. This diverts the course of the river, splitting it in two. So now, instead of there being two environments, one with just cats and one with just mice, suddenly there are three environments: one in the East with just cats, one in the West with just mice and, in the middle, a new environment that contains cats and mice.
So what happens next? Well, in the case of the first two (cat-only and mouse-only), nothing much. These two populations will continue on exactly as before. Oh, the newly formed rivers will mean that there will be less space in each, but there will also be fewer animals taking up that space (as the rest got stuck in the new middle bit). So, for each, the environment is the same and therefore life will go on much as before.
But what about the cats & mice who now find themselves stuck together in the middle? Well, for the cats, there is Good News and Bad News. The Bad News is that the river has cut them off from their food supply, so they are likely to starve. But the Good News is that they are now surrounded by mice. Scrum-diddly-umptious mice! Hooray! And for the mice…..? Well….take a guess!
And so, the obvious happens. The cats start to eat the mice. And so the numbers of mice start to fall. Now, if this went on indefinitely, eventually the cats would eat all the mice and would then begin to starve. But that’s not what happens. Actually, the cats are only able to eat some of the mice.
Why? Well, it’s because the mice are not all alike. Within any population of animals you get some variation. Some individuals are bigger, some are smaller. Some are fatter, some are thinner. Some may be light coloured, some darker. And so on. This is just as true for mice (or cats or zebras or amoeba or plankton or whales) as it is for humans. So, in our example, there is some variation in the population of mice. Specifically, some have lighter fur and some have darker fur. And that is why the cats don’t eat them all. The cats find it easier to spot the lighter coloured mice, but find it slightly harder to see the darker ones. This means that the lighter coloured mice are more likely to be eaten and the darker coloured ones are more likely to escape (and therefore survive).
Now, as this continues, the darker coloured mice will be the ones more likely to survive long enough to mate and produce offspring. And those offspring are therefore also more likely to have dark fur (although there may also be some light coloured offspring but, again, they are less likely to survive being eaten). And, so the generations go by, the likelihood of finding a light-coloured mouse will get less and less until eventually the only mice you’ll find are dark.
And this is what is known as Selective Pressure. Basically the “pressure” comes from the chances of being eaten, which “selects” the traits within the population (dark fur in this case) that have increased chances of survival.
So that is what is happening with the mice. But what is happening to the cats in the meantime? Well, initially, they will be having a Whale of a time, eating lots of light-coloured mice and getting nice, full bellies. And this increases their chances of surviving and breeding, so the population will increase. However, over time, this will begin to change. As the Selective Pressure on the mouse population starts to make numbers of light-coloured mice fall and the (harder to spot) darker-coloured ones increase, the cats will find it harder and harder to catch their prey. And so they will start to starve and their numbers will start to fall.
Now, if this went on indefinitely, then eventually the cats would all starve to death. But, as before, this doesn’t happen. Because just as there is variation in the mouse population (colour of fur), there is also variation in the cat population: some of them find it slightly easier to spot the darker mice! Therefore the cats with slightly better eyesight will find it easier to catch the darker mice and are therefore more likely to survive long enough to produce offspring – offspring who are more likely to have the “good eyesight” trait. And, so the generations go by, the likelihood of finding cats with poorer eyesight will get less and less until eventually the only cats you’ll find have better eyesight.
And so, just as there is Selective Pressure on the mouse population which makes the darker fur more likely, there will also be Selective Pressure on the cat population which makes better eyesight more likely!
And this is just the start of it. Once this process gets started, it just keeps on going. So, over many, many generations, the Selective Pressures on the mouse and cat populations will keep pushing them to change. For the mice, over successive generations, you’d start to see the emergence of better and better forms of camouflage. For the cats, over successive generations, you’d start to see the emergence of better and more sophisticated eyesight. (But remember that not every member of the population will display these traits – the populations will still show variability and only certain individuals will be “selected” for survival – so it’s not every single member of the population that changes).
Now, if this went on long enough, eventually the populations of cats and mice would have changed so much that they would be completely different to the original cats & mice who found themselves stranded by the earthquake. They would be new species! And you could easily spot this be comparing them to the population of cats in the far East of the plain and the population of mice in the far West, neither of which were subject to the Selective Pressures and therefore remain much as they have always done. And so, while the plain initially only had a single species of cats and a single species of mice, after enough generations have passed you end up with two species of cats and two species of mice!
So that basically (very basically!), is Darwinian evolution. “But how does this relate to cancer??” I hear you cry. Well…..I’ll explain all in my next post…….
To Be Continued……
Darwin, Charles (1876). The Origin of Species
By Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life Cambridge University Press DOI: 10.1017/CBO9780511694295
AG McCluskey (2016). Damn You Darwin! Pt1: Cat & Mouse Zongo’s Cancer Diaries