Despite all the beautiful and reliable mechanisms of our bodies, sometimes things go wrong and today we're going to think a bit about how we can fix things when they go wrong and particularly how these new ideas, this new science of genomics, can help us do that. So how many people have colds here today? Er quite a lot, yes, I feel sorry for you. I felt terrible a week or two ago, I had to stagger through a lecture with a cold. We don't expect it, do we? You know, in this country like the other richer countries of the world, we've solved quite a lot of these infections and we really think it's unusual. Now this room throughout the lectures we're thinking of as being a cell. That's its nucleus up there and these are the walls - it's one cell in the human body if you like. And there's a flu virus there, and this is part of the cell wall with the lipid membrane the way it is and various things poking through it and viruses get in through the cell and when they're inside, they start to release their DNA. The protein coat around falls off and the DNA comes out and starts to make the molecules that the virus needs to go on. So a virus is an invader that takes over the machinery of the cell. If we can have a look at this thing on the trolley, what is this? Ah, it's a computer disk. Let's have a look at that. Pop it in there, let's have a look and see what it does. There's an icon that's turned up saying run this to get rich - that must be an interesting thing to do, don't you think?

So that's a virus taking over the computer, in the same way as this takes over the cell. We protect ourselves against all these invaders as much as we can with the outside of our bodies and with their defences - the air channels are protected with mucus and hairs and so on. But sometimes things get inside and then they're attacked by the cells of the immune system: there's a white blood cell attacking some bacteria which you can see at the front as they try to develop inside the body. But that gives you a feeling for where we've got to with the infectious diseases. The thing to do now is to go on and talk a bit about the diseases that arise from inside our bodies due to the defects in our own genome. And to start off with we want to start a little test for you because there is a very innocuous sort of genetic disease that's very widespread nevertheless and that's colour blindness. And so we're going to try looking at some charts all of you. Now I'd like you to hold up your red cards if you can see a five in that figure, can anybody see a 5, don't be shy, there must be somebody who can, can I see there's a red one good, anybody else. I expect more, are you sure you can't see a 5? Oh there's some up there, one there tentatively - is it? No? OK. If you can see a 3, hold up your green cards.

OK, so that's right. Nearly everybody is 3, now go back to the red ones and I'm surprised how few there are. So let's see how many reds there are. Right OK let's try another one. We'll go on to the next card please and I want in the next one anybody who can see 35 to hold up their red card. Yeah. there's one there, anybody else? 35 in the thing, a few more this time. Who can see 57, here's the greens coming up right. Put those down, the ones who held up their red cards and I think they were more or less the same people every time - I think are all boys - were there any girls there who held up their red cards? One up there, yes, and boys - who held up their red cards? More boys is it? Yes, quite a few boys. In fact it's interesting how many girls there were because the way this works - and we'll see on the screen in a moment - is that this colour blindness which is very mild and doesn't bother you in every day life is due to a defective gene on the X chromosome.

Now as I guess you know, all the girls have two X chromosomes and the result is that of the defective chromosomes that are floating around in the populations . About 7% of X chromosomes have this particular defect; the girls will mostly inherit a good one as well. So they'll have the defective one but they'll also have a good one so they'll be OK. But the boy only has one chance, you see he's got the X and the Y chromosome to go with it. So if the boy happens to inherit a defective X chromosome he doesn't have another one to back it up, so it's what we call a recessive gene. OK so this is the incidence of that colour-blindness in the population and it's an example of a mild genetic disease. Now Susan - this is Susan Gribble who works at the Sanger Institute - and she's going to show us the assay for a much more severe disease called the DiGeorge syndrome. And this is a problem that arises where you've detected immediately with new born babies and it's a very severe combined problem which involves severe defects in the immune system. It involves heart problems and a whole series of other problems, but it's not that easy to define exactly because the baby is sick and there maybe other problems. So what Susan does is to get the blood from the baby and get a spread of chromosomes which you're now seeing. Those are the chromosomes that's right there up there on the screen, that's the spread of chromosomes. She's then able to probe the key regions for this DiGeorge Syndrome with a marker and at the same time she's probing to detect the chromosome which is number 22 that this sits on. And you're seeing the process as she builds up the picture here using one colour of light after another. Are we there?

We are.

Great. So would you like to show us, Susan, what we're seeing there exactly?

These are the two chromosome 22s, that's one and there's the other.

And they're shown by that green marker, aren't they? So we see the two little chromosome 22s and then …

And then this is the DiGeorge gene focused here in red and this is the defective chromosome that doesn't carry a red signal.

So the interesting thing is here not the presence of the red on the one chromosome 22 but the absence of it on the other and that's why you have to use two probes, isn't it, so that you know that the chromosome is there and you know where to look in case there's some little bit of a problem somewhere. There's a speck of red somewhere else but here we can see very plainly now it's that absence of a section and it's, it's how many it's a lot of bases missing.

This patient will probably have lost 2 million base pairs….

2 million bases, so that's a lot of genes from the region and it's the loss of those genes in only one copy in this case which causes the problem. It turns out that with some of these genes at least having another good copy of the chromosome isn't good enough. You get your syndrome just by having only half as much of those particularly genes as usual.

It's a beautiful picture and it's a very important method of diagnosing this thing. Susan, thanks ever so much. Now I mean we ran through that very quickly and I said glibly "Oh we probe the chromosomes" - but maybe you're wondering exactly how we do that and because this is so basic in molecular biology and in the whole business of looking at people's genomes we're going to try out a little game demonstration for you. I need to have four volunteers please. Let's see, I'll have you from next to Susan and then you at the end there. You, yes please. I want you to stand in a row here, and now what you're going to be is part of the chromosomes. The human genome is seriously large and what's happening with this probing is we're really looking for a needle in a haystack that's the clever bit a probe is somehow identifying the gene. So how does it do that? That's what we're going to work out. So I'm going to give you each a placard to hang around your neck. It doesn't say anything rude - it's just a bit of the sequence and so what I want you to imagine is that these are portions of those chromosomes you can see there. Ok we haven't room to try all the chromosomes but there's bit of sequence, there's a bit here, a bit there, a bit there and then lots more in-between and scattered all around. Now this, we used it before, is a model of DNA and if we unwind it that's what we've got - the two strands and the base pairs together. And when we heat DNA the base pairs can come apart. They can pull apart so that you have one set attached to one back bone and one to the other, so the two separate strands are floating around.

So when Susan was preparing the chromosomes that would be the first thing she did, she heated them so that these people would have single strands of DNA. Now this is the clever bit that when you start cooling DNA again the base pairs will start to reform and if you cool slowly enough they have a chance to find their proper place. Now over here we have similarly base pairs which have been melted so you've got single pieces of DNA, single strands, but these as you'll see in a moment are all the same because these are the bits corresponding to the gene we're looking for. So I want each of you to go up to one of those people and try and match your placards together you're going to do it this way, sort of bottom to bottom and see if you can match the base pair like they are. Off you go, each person choose one bit of chromosome to go to, no, you just go to one and stay there. Now then can anybody see whether they've got a match according to the base pairs on the, on the top there, how about this one, how does this look, is that, is that right, no that's still not right now what about this one, how are you doing, do you think you've got one, yes you've got the match, you should have been confident. Put your hand up. Anyway there it is, there's the match look TA, TAGCGTACG 80. Now what will happen is that as we cool the thing and the base pairs start to reform is that these will stick together. OK and now I'm going to be a whole load of water molecules, because the next thing Susan have done would have been to wash along, but remember the bits of chromosome are rooted to the spot. The original people out there can't move because they're glued down to that glass slide but the flashing probes are free to move if they're not properly based paired. The probes that aren't attached are going to disappear down the plug leaving the one flashing light attached to here and so this probe has found it's target, it's found in this case the DiGeorge gene.

And this is an extremely basic method, this finding the needle in the haystack of the genome, this seriously large thing, 3,000 million bases in one copy, 6,000 million bases in every cell. We have got to have methods by which we can seek it out and due to this magic of just a few base pairs what we actually use are a little bit longer than this, but not huge just a few tens of bases we can find those places and do what we want to do with them. So thank you very much to the volunteers for showing us so well.

So now we're going to go on in a moment and look in more detail at a very serious genetic disease.