Damaged DNA

28 September 2008

Interview with

Steve Jackson, Gurdon Institute, University of Cambridge

Helen - Why don't we feel as young as our youngest cells? The answer could be the damage to our DNA due to exposure to radiation or toxins or just the copying errors when our DNA is replicated. Professor Steve Jackson joins us now from the Gurdon Institute here in Cambridge University. His team are trying to understand better how DNA becomes damaged, how this damage relates to disease and how to repair damaged genes. Hi Steve, thanks for coming on the Naked Scientists.

Steve - Hi

Helen - So how does DNA become damaged in the first place?

DNASteve - There are a tremendous number of ways that DNA can become damaged. We are all aware of the fact that if you sit in the sun too long the ultraviolet light can damage DNA, so chemicals can. Radiation use, for example in radiotherapy, can damage DNA. Actually the largest source of DNA damage is oxygen. About 2% of the oxygen we breathe actually gets converted into things called reactive oxygen species in the mitochondria in our cells. Some of that escapes. That, together with hydrolytic reactions catalysed by water are occurring all of the time in our cells, even if we are sitting in the dark away from everything else and not being exposed to any chemicals. The amazing thing is that we have around 1014 cells in our bodies and every cell in our body is sustaining around 100,000 lesions per day. Our bodies, even if you're not sitting in the sun and you're not exposing yourself to any other chemicals, are having to deal with somewhere in the region of 1018 to 1019 lesions per day.

Helen - Is that lesions in the DNA?

Steve - That's damage to DNA, yes.

Helen - So our DNA is being damaged all the time, but why does this now lead to disease?

Steve - Well, fortunately the vast majority of that DNA damage gets detected very rapidly by certain specialised proteins in our cells and gets repaired. So the vast majority of that DNA is repaired. Some of it isn't, it escapes these surveillance pathways. That damaged DNA, when it eventually is put back together again, often has errors which are mutations. Those mutations can mean that the cell isn't working in the way that it should.

Helen - You mentioned the surveillance, now this sounds like there is something fantastic going on in our bodies to try and undo this damage that is happening to us on a daily basis. So how can we actually repair our own DNA, what's going on inside the cells?

Steve - Well if we didn't have these surveillance pathways we wouldn't last very long. The fact is that most of the DNA damage that is occurring is repaired. What my lab and other labs in this area are working on is trying to understand how these "molecular policemen" work. Really they are molecular policemen that patrol the cell looking around for damage, not doing very much, but when they stumble across damage, as it is occurring all the time, they jump on the DNA. They then send out signals for the cell, alert signals for the cell to stop doing things such as dividing while the damage is there, then hopefully repairing that DNA damage in a way that doesn't generate mutations. These pathways work very well but occasionally they go wrong and that can lead to mutations that can contribute to diseases such as cancer and we believe it can also contribute to ageing.

Helen - You touched on the idea that we might be able to do something like use these mechanisms of repair ourselves and actually promote that kind of repair. Is that something that we're actually seeing happening already or are these just still ideas to mimic those actual repair mechanisms?

Steve - I think ultimately it should be possible to find ways of improving these surveillance/repair mechanisms. If we could find ways of improving them I would place a bet that it would slow down at least some aspects of ageing, maybe not all of them. The problem is that our cells are working very efficiently already so trying to find a way to make them work even better is difficult. One very interesting idea is that many pathways, just like the police forces or other surveillance systems, can work in a latent capacity or can be induced. There is a growing body of data now showing that a little bit of stress to the cellular systems can hyper-activate these repair pathways. So I think one of the major opportunities might be finding ways of boosting our defence systems by making ourselves in this higher state of alert. If we could do that or find drugs or other ways of bringing that about then that might actually slow down ageing at a cellular level.

Helen - So if we could tease ourselves into thinking there is a little bit of damage going on perhaps, or mimic that, then the cells might actually kick in that repair mechanism and help repair the damage to the DNA.

Steve - Absolutely. I think even some things that we know might contribute to slowing down ageing, at least in some regards, such as exercise, might be exerting some of their influences by stressing our cells and we know that stress tends to induce these repair and other pathways.

Helen - So a little bit of stress might be good for us.

Steve - That's what I keep saying to my students.

Helen - So do you think we could ever stop ageing altogether, or is this something that is such an inherent part of life that we're never going to overcome the fact that DNA suffers so much damage as we live our daily lives?

Steve - I think it will be very difficult to find ways of reversing age, or even stopping it. As I pointed out earlier on, much of the DNA damaging chemicals, such as oxygen and water, are intrinsic to life. It's very difficult to have a system that is 100% accurate in terms of repairing damage. Having said that we know that different mammals can live tremendously different lengths of time so it is possible for an organism to develop in a way over evolution to live much longer or live less long. I think if we understand all these pathways and also understand why some organisms live longer than others we may be able to find ways of tweaking the system to make us live longer.

Helen - If it isn't just a case of living longer but perhaps improving certain parts of our lives. Is there anything in particular that damage DNA - apart from diseases - are there any other aspects that we can work at improving through maybe mimicking these repair mechanisms? Are there other aspects of ageing in the body that are really the crucial things that we would want to look at?

Steve - I think it's very easy to think about ageing as a superficial thing such as the greying of your hair or the wrinkling of your skin. The reality is the ageing has a range of diseases associated with it. That includes neuro-degeneration, cardio vascular disease and cancer. We know from working with a number of labs including ours that defects, or problems with these DNA repair mechanisms, can lead to cancer. We also know that they can lead to neuro-degenerative disease and there is growing data suggesting it can contribute to cardiovascular disease. So I think ageing shouldn't be thought of as a superficial issue. Ageing occurs in our organs and our brains and I think these are the kind of diseases that we might be thinking about alleviating

Helen - Thanks Steve, that's Professor Steve Jackson from Cambridge University explaining how stopping DNA from getting damaged could lead to longer, healthier lives.

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