Patchwork of mutation - Raheleh Rahbari

Photo supplied by Raheleh Rahbari

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Kat Arney: As Andrew mentioned, there’s a lot going on in our bodies as we get older, including the gradual pileup of mutations in our cells. But, as Raheleh Rahbari and her colleagues at the Wellcome Sanger Institute in Cambridge are finding, there’s more to this phenomenon than meets the eye - especially when it comes to the distinction between the immortal cells of the germline - which make eggs and sperm to create the next generation - compared to the rest of our bodies, known as somatic tissues. And to find out why, we need to go right back to the beginning. 

Raheleh Rahbari: So actually this is a kind of interesting open question. So we all start the same by a fertilised egg, which essentially sperm and egg generate this fertilised egg, and we all start our life with one cell, and this cell goes through a lot of division replication to generate a volume of a body, and this will undergo obviously ageing and we start seeing changes throughout ageing. And it is really fascinating to be honest, because as you said, we start with one cell, but then how we change and how people during a natural process of ageing acquire different diseases, for instance, like cancer neurodegenerative disorders, it's really an open kind of question.

What happened in our DNA, in our genome, in our body that maybe predisposed some to, for instance, diseases like cancer, some others to neurodegenerative disorders. We really don't know much about it, and in recent years with a lot of effort in the scientific community, we started identifying some interesting information about how a single cell starts changing during life and may cause disease during adulthood and ageing.

Kat: So let's look at where this actually starts because you look at a baby and they look pretty perfect. You know, they're all nice and beautiful. But, even at that stage, are their differences between the cells at this level of the DNA? When do cells start picking up changes and becoming different because we sort of have this narrative that all the cells in our body are the same, they have the same DNA, the same genome, but when does this actually start becoming different?

Raheleh: Absolutely. So even monozygotic twins that are generated from one cell, we now know that there are actually genetically different. So even though from very early on, we all look the same and we all start from one cell, even in the twins that share even one single cell, we start seeing the effect of ageing. And this is because the hallmark of ageing is accumulation of changes in our DNA, which is called mutation, and this is essentially a result of physical damages that cause to our DNA during the process of replication.

So cell, as I said, has to divide, to generate our body and also fulfil the volume which is required for different tissues to function. So we have a very great mechanism in our body that repair any physical damages that happen into our DNA, and during this repair mechanism a mutation happened, these are the changes in the DNA that essentially our repair machinery does not recognise them. So as much as it is a perfect machinery, yet it is not that perfect, like hundred percent perfect and we still acquire mutations and changes in our DNA. So as from the very first cell division, we start accumulating changes, obviously these changes in the DNA not always cause disease or cancer, and these are the natural hallmark of ageing, so we should not be worried about it, but something we don't know is what happens when mutation accumulate and changes in our DNA accumulate, at what stage they start changing into causing disease. And this part is really fascinating area that we are trying to understand.

It is not really easy to essentially address detection of these DNA damages or mutations in a cancer setting. In a tumour is a lot easier, I'm not saying it is an easy task, but it's a lot easier than looking at the natural changes that happens in our cell during ageing. So we can study cancer data and tumour samples, identifying the changes in the DNA and compare it to what actually are the changes in a natural ageing DNA, and maybe by subtracting this subset of mutations, we can identify the causal mutation that relate to, for instance, cancer or neurodegeneration.

Kat: I find this so interesting because there's a lot in what you just said. I think one of the first things that's most interesting is we have this idea that mutations are caused by things outside us. You think of the obvious stuff like tobacco smoke or the ultraviolet radiation from the sun or x-rays or nasty chemicals that all mutations come from the outside and damage us. But it has always surprised me learning the extent to which just the processes of life within ourselves, this process of DNA replication, just the actions of metabolism, how our cells make energy is damaging to our DNA. And I think that's a quite a surprising story to many people.

Raheleh: Indeed, and this is definitely inevitable. Obviously, as you correctly said, there are exogenous factors like smoking, drinking alcohol, different dietary habits that can cause extra changes in our DNA and may cause a mutation. However, even within our body to function and to age naturally we do accumulate mutations and this is something we cannot really change.

Kat: So let's take a look at the way in which our bodies change through life. So to what extent are we finding these changes in the tissues of our body? Does it go okay and then suddenly it all goes crazy? And is it different in different parts of the body?

Raheleh: This is really interesting question. So we didn't know much about variation in terms of how changes in DNA happen in our different tissues within one individual. So if we compare, for example, colon from brain from liver, did all these tissues accumulate mutation in their DNA at the same rate, or is it actually different?

So in our recent work and ongoing work, what we are trying to identify is actually how this mutation may accumulate in different tissues. Do we see variation? And indeed recent results, and a study, do show that there are variation in terms of how mutation and changes in DNA accumulate in different tissues. We can see that, for instance, colon from someone who has age of thirty and is normal, accumulate less mutation comparing to someone who has age of eighty. This looks like a linear accumulation of mutation, so as we age per year, colon tissues do accumulate mutation at a constant rate and this accumulation of mutation recently, we noticed that actually might be variable across different tissues. So it looks like that some tissues do accumulate mutation at a very low rate. For instance, in testicular tissues from men, we realise that actually accumulation of mutation is a lot lower than his colon, and this is very interesting because they have inheritance consequences.

So if there is any changes in DNA in the testicular tissues, specifically in germ cells, they have inheritance consequences. So they can actually pass to the next generation, to the children. This is really fascinating because it shows that there is evolutionary pressure to keep mutation in this tissue a lot lower and possibly protect the germ cells from acquiring mutation because of their evolutionary role.

Kat: In some ways, this discovery that normal tissues have a lot of mutations, It doesn't really feel very new. It feels like for a long time we've just sort of said, "Oh, our cells pick up mutations as we go through life", But it feels like maybe we're really just starting to get it as a field. Does it feel like that?

Raheleh: Yeah, definitely. I think, as you said, we did know for somatic tissues, such as colon, we knew they accumulate mutation with age, but something now we start understanding a lot more is the extent of mutation, the extent of burden on different tissues seem to be very different.

So from a recent study and investigation that we are doing to interrogate mutation burden in normal tissues, we actually identify the burden on a digestive track is a lot higher than the other tissues in the same individual. And this is actually quite an important concept to understand. Why do these tissues, that are within the same person, do accumulate mutations at such a higher rate? Sometimes we see twenty four differences within our tissues, so some tissues keep accumulating mutations on a daily basis and some mutations have a very slow rate of accumulation of mutation.

So yeah, I think as a whole, as you mentioned, we did know that as we age, we accumulate mutation. But the extent of it and how much variation we are starting to see in different tissue. I think this opens a very new, interesting era to start interrogating and maybe identifying the mechanism that cause accumulation of mutation across different tissues and their relevance to disease.

Kat: Raheleh Rahbari from the Wellcome Sanger Institute.

Photo of Raheleh supplied by Raheleh Rahbari