 Dydyn nhw, mae gwnaeth gwybod… …rydych chi'n gwybod a gyddon y ddysgu… …lyny'r ddynnu,cottibwyr o'r process. Mae'n rhan o'r ddydu fwylltio..] gwybod o'r ddysgu. Mae ydych chi'n gyw, mae gennym o mi, i fynd i'w gwybod o'r ddysgu. Tynnau hynny. Felly, robbed, mae mae buddyn nhw, i ddynnu hyn yn ei gwbl. Mae'n ddynnu am oed gyfer ei gyd-dynnuд ac mae Gwchwyn fyddai gwbl. a hynny'n ysgrifennu gwahanol dros y ddigon i'r ddyfodol. Mae'r ddweud iawn i'r dros y Gwein Victoria, yr hyn yn bocs sydd y ddyfodol yn fwyaf hynny'n hynny. Oherwydd mae'r gennym iawn gwahanol, dros y ddweud iawn, yn fwyfio'r ddweud iawn, a'r ddweud iawn i'r ddweud iawn. It would be great if there is something lambda forGive at them. But To do that you have to get all these people to agree which isn't that easy people don't like being taken part even if it's a simple test like spitting into a tube or taking a blood sample You have to find out the entire family history what environment or whether they exercise what food they get and look at the length of time from Queen Victoria down its six-seven generations potentially hundreds of years to figure out what's going on gyda'r cyfnod. Yn ymchwil i adael wych chi, ac wedi'i gwestiynau, y nesaf, yn rhan. Y vow datblygu, ratio'u gwirio'r gymorth yma yn y Cymru ac mae'n gweithio'r gyflymhyt trydedd raspberryll Cymru. Mae cyfnodd ar gyfer mwybu ar gyfer mwybu ac ar gyfer mwybu er ein gwybod, ac mae wedi ei bod ymddir yn wych yn gwneud, ond mae'n gweithio. Os ydych chi'n oedd y gweithiol yn y rhan o'r llwy. gyda'r genedlaeth, y rhaid i gyllud, y rhaid i ddweud ychydig, y llwyfrifol yw'r amser, ymweld i'r ysgrifennu a'r andyniad ar gyfer ymgyrch yn y cyflogol yn y ddeallu'r ddeallu, ychydig i'r ddweud. I'r ddeallu wedi'r ddeallu sy'n gwybod i'r ddweud i'r ddeallu, neu i'r genedlaethau, ac yn rhaid i'r ddweud i'r ddweud i'r ddweud i'r ddweud i'r ddeallu. Ac y cwrnod, mae'n trafodaeth yma i'r cwm o'r fath am y byd hwn i'n fath. Mae'n bryd o'r fath am y byd o'r fath am y bydd hynny'n fath. Daen nhw'n meddwl am y pwg wrthoedd ym Mhwngur yw'r gweithio cyllid yma'r meddwl o'r ymddangos yma ar y cyfrifau llwythgoedd, a'r fath i'r byd hwn i'r hynny'n fath, mae hwn i'n gwneud arno ar y gweithio ar y ddweud. Felly mae'n cyntaf, ond mae angen i'w ffordd o'r wneud. Mae'n dweud i ddweud eich bod yn ymwneud. Ond ydych chi'n gwneud ymddiol? Yn y gweithio, mae'n gweithio, ond rydyn ni'n ffru咪'n gwneud y genedig ar gyfer gweith. Dwi'n gweithio ar gyfer gweithiol ac yw ddweud i'r cyffredin i'r cyffredin. Mae'n gweithio'n gweithio, ond mae'n dweud i ddweud i gweithio ar gweithio ar gyfer gweithio. a llwyddoch i Gwyrd Llywodraeth, Deffnus, Lwyddoch i Gymru Llywodraeth, Llywodraeth, Ddwylliannus, Ddwylliannus, Diabetes, Obesity, dweudio cyfreidog hwnnw. Maen nhw'n meddwl arweithio'r cyfreidog erbyn. Fy hwnnw'n meddwl ar gyfer y cyfrifiadau meddwl, yn Llywodraeth C. A oedd hynny'n meddwl o ffyrnau. Dwi'n meddwl i gyd-dwylltio'r llefion yw'r meddl. Wrth gwybod ynddyn ni'n cael eich bod yn disoffolaeth, iddysgwyr, ond yna model yma, ond yw'n cael ei ddechrau. Rhyw ddweud y dymeidoedd hwnnw'r bod hwnnw hefyd yn cael ei meddwlhygon iawn. Rhyw ddweud yma yma hwnnw dafod o holl arddangos ei meddwl hefyd. Erth gweithgwyr wedyn yma yma'r hyn yn ymgymlffydd i gael. Phu yw gerd-dwyllwn ar maen nhw wedi'u meddwl hwnnw— Ie ddweud y ddweud o'i bwysig, a ddweud o'r ffordd o bwynt o'i ddweud o'i ddweud. Cymru'r ddweud o'r ddweud o'r hunain yn fysg. Mae'n hollu'r cynni, mae'n hollu'r rhan. Mae'n hynny'n ffodol, mae'n hollu'r defnyddur, mae'n hollu'r oestiol o'r rhan. Mae'n hollu'r ddweud o'r hynny'n hollu'r hollu'r hwn o'r ddweud oherwydd oherwydd oes y genneidol ac y gallwn amddangos yn gwirio'r genomem. Mae'r rhan o'r clywed o'r probosion o'r cyfnodd cyfnodd. Felly, dwi'n meddwl'n gwirio, drwy'n meddwl y gallwn i ddefnyddio genetig cyfnodd. Dw i'r rhan o'r problemau o'r genomem, mae'n cael ei wneud. Felly, mae'n gwirio'n cyfnodd cyfnodd cyfnodd, a dwy'n meddwl am dyn nhw. Felly rydym wedi'r ymgyrch. Mae'n ystod i ddweud o'r cyfnodd, ac mae'n gofyn o'r ffordd o'i gwyllteidiaeth a'i gael ei wneud o'r ffordd. Rwy'n gweinio'n gweithio'n gweithio a'n gweithio'r ffordd o'r ffordd o'r hyn. Rwy'n gweithio'n cyfrannu yn ysgrifennol, i'r genetigau, ac y bydddol yn gyfarwyddol. Rwy'n fynd i'n gweld y dyma'r cyflodyno'n gweithio. Mae'n gwaith eu cyfrannu, mae'n gweithio'n gweithio'n gweithio,wert gyda'r un ddefnyddio'r ysgol ymdnadgoedd. Felly, mae'n gwneud diwrnod eich parff ymlaenfodol o'r hyn syniad. Ond mae'r cwmnydduron t Startwyr yn j gerdynt yn fwy iddyf, ac mae'n gwybod eu fflaen fygledd eich llwyteru'r hyn. Rwy'n gwybod i nodi gan bod eich parff ymlaenfodol a'r hyn o'r dweud eisiau geisgol. Brannu ymlaenfodol eich parff iawn yn mi o gweld,'i ddysgu'r mewn. ond, idrym eich gweithio,icaer, i chi wedyn yn ytafod gyda gyda gyda gyllidol. 90% o gyllunau ffyrdd yma arall yn eich gelwyr effaith. Mae ffasma yw gweithio, yna'r unrhyw ffaith, mae nhw'n ddweud yn y bwysig yn ei wneud, ac mae'n ddod, ac mae mae'n ddweud arall yn mewn amser o lawr, ac mae'n gallu rhoi ar gweithio a'i trydymu'r Dramaig, Felly, mae'r cwestiynau diwethaf y bydd yn amlyodd o! A'n wych yn rhoi o'r gwleidach, gallwn i'w pwlethau'r wych ac mae'r gymryd yn rwynt ation eu amser. Ond mae'n llwyื่os hefyd ychydig i'w siarraedd leolodau, oherwydd mae'r gyffredig os yr holl. Mae'n meddwl yr hyn yn rwy'n meddwl, mae'r chydoedd. Mae'n meddwl i chi'r ychydig, mae'n meddwl i chi'ch chi'ch chi'ch chi'ch chi'ch chi'ch chi'ch chi'ch chi'ch chi'ch chi'ch chi'ch chi'ch chi'ch chechod. So mae'n gwneud, mae'n ddechrau, byddwn i'r cael ei ddau apartwg at yr oed. Saedd gennym ni'n gofio, rydw i'r language ond mae'n adrodd yn cymaint ei ddweud. Mae'n gweithio ddechrau a gwneud. Pryddoedd maen nhw ddweud o'r iddynt ei syniad, mae'n rhowch ac eich rhaid i ddedigol â'r sgwrs rydyn ni'n rhaid i ddechrau. Mae'n gwneud, yn y bwysig, pan onad 2,2 miliwn ymgweithio? Mae'r cost rheswun y gweithio rheswm wedi'u'i hwnnw, i'r llwyso, y dyfodol yn 4 billion. Felly, mae'n ffordd yw'r ddweud yn ddweud, mae'n gweithio'n ddweud. Mae'r ddweud yn gweithio, a'n ddweud yn fwy o'r cyffredinol. Mae'n mynd i'r ddweud cyffredinol, mae'r ddweud yn fwy o'r ddweud, yn ddweud i'r ddweud, yn ddweud ar y cyflodau a'r ddweud 300 miliwn. Felly, mae'n ddweud yn ddweud. Ac yn fwy o'r ddweud, mae'n ddweud i'r ddweud. A oedd yn y ffordd yw'r ddweud, yn y mawr, mae'r ddweud yn ei wneud o'r ddweud, ac mae'r ddweud yn ddweud. Felly, mae'r ddweud yn hollu'r cyffredinol. Mae'n hollu'r cyffredinol, mae'r ddweud yn hollu'r cyffredinol a'r ddweud yn hollu'r cyffredinol. Byddwch yn oddiadus anghybau'r cyffredinol, wrth yn idau cyflwyno Seid yna y gallu amser yn fawr. Felly mae'n meddwl i'w hoffa ni. Felly mae'n meddwl i gyhoedd. Mae gyda'r ddiweddol hwn yn fwy, mae'r ddefnyddiad Cymru yn ymgyrchol, ac mae'n meddwl i'w hoffa ni, ac mae'r ddodlai, mae'r ddodlai, mae'r ddodlai sydd wedyn teimlo i bob ddweud i ddwy'r cyflwytoedd. Felly, yma mae'n meddwl i'w hoffa ni? Felly, gallwn gwybodaeth, mae'n meddwl i'w hoffa ni eisiau. theres a lot of association with a bacterial infection. Most children get it, they get a bit of a feaver, the get a bit of a snotty nose, they get a bit of gluure and then it results. So it does seem to be associated with a bacterial or viral infection but for decades they've been researching this. We can't actually find what bacteria, or pin it down, is it associated with infection. gyda'r infeksym, ac mae'r creunio cysylltu'r bwysig yn y bacteiriad yn y cyfnodol, yn y bacteiriad. Rhaid i'n ddweud y bacteiriad, mae'n gweithio ar gyfer amser ac yn ffantyr. Rhaid i'n ddweud, mae'n gweithio ar gyfer amser, mae'n gweithio ar gyfer amser ac yn bacteiriad. Mae'r paniau amser, fel y gwirionedd, yn gweithio ar gyfer amser, As you may have read from the press, MRISA, drug-resistant bacteria are a bad thing, so we try and limit, the clinicians try and limit how much antibiotics are prescribed. It's not that effective, so it costs a lot of money to give these kids, there aren't antibiotics, it's a risk to society in the general and it doesn't work that well. The only known treatment that works relatively effectively, but even then is not a cure, is the placement of a gromit in the eardrum. Now, it's the most common cause of surgery in children under the age of five. Surgery in children is not a good thing, there's always a risk with any surgery of infection under the anesthetic and it's stressed to the family and the children. Now, a gromit is simply a tube that they push through the eardrum and it allows the fluid to drain out. We don't know how it works, but it seems to work in a lot of cases, but some people have to go through multiple rounds and it means you can't go swimming, the tubes drop out, you have to have them replaced and things like that. It costs money, you know the situation we're in at the moment, we have to look at ways of reducing costs, obviously not affecting people's health, but this is a high cost and a high risk to children. So there's a big question, what causes OM? Why do some people get it and get over it and others have it for the rest of their lives and have to go through multiple rounds of surgery? So human studies, one way of looking at the effect of genetics, so the question was, is it bacterial infection or is it genetics? One way is twin studies and triplet studies, because twins are genetically identical, if they both get the same disease there's probably quite a strong genetic component and the estimate from lots of human studies was about a 70% genetic component. There's also quite a racial variation, some racial groups seem to be more prone to OM than others, so that again hints at genetics and also Down syndrome is strongly associated with gluear. There was a sort of story that came out that it might be the way your shape, the shape of your face and the shape of your ear, so that your middle ear can't drain properly and that's why people are more susceptible to OM, but it never really got anywhere and was never really proved. So one of the key successes we had at Harwell was identifying not one or two, but we've got now three and potentially four different mouse strains that develop otitis media and immediately this has told us a lot about the genetics of OM. So first off, that's an affected mouse, that's a normal mouse, they're a bit smaller, the other strains aren't smaller, but they all get OM spontaneously. One of the first things, this is what the middle ear looks like, it's full of these inflammatory cells, absolutely packed, it's a bit like pus, that sort of stuff, hence why it's called glue, it's all gloopy. This brown staining is a chemical you can label the cells with, what this is telling us is that the middle ear, these cells are hypoxic, so that means there's a lack of oxygen in the middle ear. Now one of the real questions was, if people are prone to this inflammatory disease, why do they only get it in their middle ear, why is that so special, why don't they get it anywhere else? And it turns out from these studies, the middle ear seems to be hypoxic, it's not oxygenated very well, and this may interact with the genetics to result in inflammation just in the middle ear. The second thing that is very important, none of these mice have any craniofacial abnormalities, they're normal mice, so it looks like it's not a craniofacial thing, it's not the way your face is shaped, it's the genetics. One of the most important things is, because of the health status of these mice, these mice are checked continuously for infectious organisms, we know they don't have any bacteria, we know they don't have any viral infections, and in fact we've put one of these mice into an environment where there has no microbiological organisms at all, and they still get OM, so there's a clear genetic link now. We've shown that genetics can lead to OM, it's not only infection. With three genes, we've mapped the genes in three of them and are looking at the fourth potentially now, identifying the gene tells you one thing, okay this gene's associated with disease, but you can then actually start working out pathways, what do those genes interact? And because we've got three of them, do they all interact with the same pathway? So if we can start identifying pathways up and down from those genes, we can start maybe saying okay well if that pathway is affected how can we modulate that pathway and help the disease. One of the genes we've taken, we found the gene in the mouse, and now we've started looking specifically in humans, and actually in the human studies, because they never looked at this gene before, they've now looked at it and it is linked to OM. So it looks like one of our mouse models is validated, it seems that humans have a similar problem to these mice, so we're now starting to understand human disease a bit more. So like I say, because we can identify pathways, we can start identifying treatments. We don't just throw random drugs, animals and hope something works, we've identified a pathway and one of those pathways is a pathway that responds to a lack of oxygen. So the ear has a lack of oxygen, we've got three genes, two of which we know interact with the same pathway that responds to a lack of oxygen. So can we modulate that pathway? So it's a bit of a complex slide but it's actually quite simple. So this along the bottom, the longer the bar, the deafer the mouse is, which means it's got more OM. In red are the normal mice, in green are the mice that spontaneously get OM, and in blue the mice are treated with various drugs that we know interact with this pathway. And as you can see, we've identified a number of drugs that can modulate this disease. So the hearing improves, the inflammation goes down and the disease appears to improve. Now I'm not going to claim we can now go out and give people these drugs and cure OM. This is just the first stage. There's a pathway that we know, there's a pathway we can potentially modify, but we have to look at the dosage. It's no good if we have to give people these drugs continuously for the rest of their lives. Ideally what we'd like to is to treat them and cure them without supplying them with drugs for the rest of their lives because drugs have side effects. But this is a first stage. It's a very exciting stage. It's the first time that a drug that isn't an antibiotic has been shown to modulate disease, modulate OM. So what else are we doing? Now because we know the pathways are involved, we can start doing more detailed studies. So leaving aside the mice, we're looking at individual cells. How are those pathways affected in individual cells? We're looking at further DNA changes. Can we find other genes associated with disease, either from human studies or from mouse studies? What is the effect of bacteria? Does it make the disease worse? Because these mice don't have bacteria, okay, what is the interaction? If you get bacteria, does the disease get worse? Do they not affect it at all? All those sorts of questions have been asked. And also, drug therapies, like I've shown you, we're identifying drugs that can modulate disease, but not only drugs that modulate diseases, how do we deliver them? People don't want injections in their middle ear, and we want a way of delivering a drug to the right place in your ear. You don't want to take pills all your life. And so because we're based on a physics institute next door, we're actually talking with a physicist that's doing a lot of nanotechnology. So can we package up these drugs and deliver them in a specific way that will cure OM in the mice? Once we start showing it works in the mice, we can then go on to human studies. And the ultimate aim is to develop a non-surgical intervention, so we can give children a course of drugs, alleviate their OM, they won't have to go through surgery, their development isn't held up. And again, you know, I don't like the word cure, but certainly alleviate the disease. So just to summarize, what have we learned from, this is just one disease that we're investigating at Harwell. What have we learned so far? Well, there is a strong genetic effect. We've shown that. You can modulate the genome and get OM in these mice. And we're in constant contact and have a joint project with people looking in human disease. So we're taking their information and looking in our mice. And they're taking our information and looking in our human studies. Efection doesn't seem to be essential for the development of this disease. That's a new story. And we know that because our mice are clean. We know the health status, which is always difficult to prove in humans. Because again, the classic problem with humans is you only get to them once they're sick. So you don't know whether the bacteria in their ear are there after the disease or before the disease. The lack of oxygen in the middle ear might explain how the grommets work. It's always been assumed that they allowed the fluid to drain out, which improved your hearing. But actually what it might be doing is letting oxygen in to an area where there's not much oxygen. And we know these genes that are affected in the mice interact with that pathway. So the oxygen may downregulate the inflammation. So we're looking at that. And again, we're looking at that in vitro, so in a dish, in a tissue culture, because we've identified it's in the mouse. And also we've started to identify drugs. The drugs we've identified may not be suitable today to give to a human, but that's the ultimate aim. We've identified a pathway. We've identified a class of drugs that can potentially modulate disease. And really, this is the ultimate aim of everything we do. It's a better understanding of disease. And not simply just human. Most animals get these diseases as well. A lot of the drugs are developed for veterinary work as well. But it's a constant circle, getting information from human studies, applying it to our research and taking our research and talking to clinicians. Most of the collaborations we've got are with clinical scientists or pure clinicians. They don't know about the genetics of mice. We don't deal with patients, but by talking to each other, we hope to understand and develop better treatments for people. I think that's it. Thank you very much.