1 00:00:00,970 --> 00:00:07,960 David, besom your fill of some cross. College Oxford and professor in molecular neurosciences here at the University of Oxford. 2 00:00:07,960 --> 00:00:13,960 David, when did you come to Oxford? And then when did you come to some cross college? 3 00:00:13,960 --> 00:00:22,960 So I came to talk to them quite a while ago. In fact, was in 1988, the spring of 1988. 4 00:00:22,960 --> 00:00:31,090 When I came to Oxford to work at the then half built Institute of Molecular Medicine, 5 00:00:31,090 --> 00:00:39,330 which was a project of Sir David Wetherall, which is now known as the Wetherall Institute of Molecular Medicine. 6 00:00:39,330 --> 00:00:45,130 And in fact, I think I can lay claim to doing the first experiment that was ever done in that building. 7 00:00:45,130 --> 00:00:53,620 So I came with Professor John Newsome Davis, who had just been made professor of clinical neurology in Oxford. 8 00:00:53,620 --> 00:01:01,450 And I came from the Royal Free Hospital, where he was previously to be part of his group or his research group at the 9 00:01:01,450 --> 00:01:06,070 Institute of Molecular Medicine and some cross colleagues much more recently. 10 00:01:06,070 --> 00:01:12,220 I'm afraid that's much more recently. So that was probably around about five to six years ago, I think. 11 00:01:12,220 --> 00:01:15,940 And I was up at the John Radcliffe site. 12 00:01:15,940 --> 00:01:20,830 I've been there all my 30 odd years here in Oxford. 13 00:01:20,830 --> 00:01:25,850 And one of the things about being up in my sort of. 14 00:01:25,850 --> 00:01:32,690 Hospital site is that, in fact, it is quite difficult to get down to be part of the university life. 15 00:01:32,690 --> 00:01:41,420 So in fact, eventually when I was offered the position of a fellow with St Cross, it was, you know, a great opportunity. 16 00:01:41,420 --> 00:01:46,220 And it is something which we perhaps miss when we were up in the medical sciences, 17 00:01:46,220 --> 00:01:53,750 up at the hospital sites to actually interact more with university and people doing nonmedical subjects. 18 00:01:53,750 --> 00:01:58,280 And so I was very pleased, in fact, to be able to take up this fellowship. 19 00:01:58,280 --> 00:02:07,010 And it has led to one being able to interact with people on a wide spectrum of different speciality is who are 20 00:02:07,010 --> 00:02:15,650 obviously experts in their field and thus obviously provide good conversation and are very interesting to meet. 21 00:02:15,650 --> 00:02:24,260 Fantastic produ. I ask you how your research could you speak a little bit about the early days of the Institute for Molecular Medicine? 22 00:02:24,260 --> 00:02:31,160 Those must have been exciting times. Well, I'm not sure how exciting our first few years. 23 00:02:31,160 --> 00:02:38,960 It was just a building site and there was dust sheets everywhere and one was trying to get one's rather delicate 24 00:02:38,960 --> 00:02:47,420 experiments to work when these hammer drills were going and needles were being shaken all over the spot. 25 00:02:47,420 --> 00:02:56,870 So it was an interesting experience. In fact, most my first few years there, I was always dealing with building work going on. 26 00:02:56,870 --> 00:03:06,260 But it allowed us to really sort of get the idea of molecular medicine and the potential for translating 27 00:03:06,260 --> 00:03:13,820 what was then really a fairly new subject into actual thinking about clinical practise and the whole 28 00:03:13,820 --> 00:03:23,360 idea of gene cloning of DNA and how you can sort of use the knowledge that was just emerging about molecular 29 00:03:23,360 --> 00:03:30,680 biology and think of how potentially that might be actually translated into the future of medicine, 30 00:03:30,680 --> 00:03:35,900 which is very much in progress now, very much in progress. 31 00:03:35,900 --> 00:03:43,150 So could you describe your research now and and tell us about what its implications are? 32 00:03:43,150 --> 00:03:47,030 Right. Well, as I said, I've gone back quite a long time. 33 00:03:47,030 --> 00:03:58,700 And actually, even before I came to Oxford, my first work on research was essentially at the very early, early beginning of gene cloning. 34 00:03:58,700 --> 00:04:09,470 So, in fact, we I was some at Imperial College to do my HD, but was farmed out to a drugs company at the time called G.T. Cell, 35 00:04:09,470 --> 00:04:19,250 who were perhaps the only people who had the or could afford and had the very up to date facilities on doing gene cloning and its very early days. 36 00:04:19,250 --> 00:04:27,920 And the first experiments we did were done in a sort of very stringent conditions where everything was sterilised before you went into the room. 37 00:04:27,920 --> 00:04:38,710 Every boy thing was fumigated after the room. And what you'd now do just on the benchtop open was done under very stringent conditions. 38 00:04:38,710 --> 00:04:43,150 So and in fact, I was taken on there. 39 00:04:43,150 --> 00:04:48,670 I wanted to go and work on cancer and interfere on some might cure cancer. 40 00:04:48,670 --> 00:04:58,150 All of that was, we were told, back in the 1980s. But in fact, when I went for my first interview, I was told that the post was already taken. 41 00:04:58,150 --> 00:05:09,580 But there was another project on Style Calyon receptors and cloning the genes that encode acetylcholine receptors that would I'd like to do. 42 00:05:09,580 --> 00:05:14,440 I knew nothing about acetylcholine receptors before. Well, I might as well go for it. 43 00:05:14,440 --> 00:05:20,870 And from this moment, I've essentially been working on the same thing ever since joining John Nuisance, 44 00:05:20,870 --> 00:05:25,150 David's group coming to Oxford and then working on this subject. 45 00:05:25,150 --> 00:05:35,110 So the acetylcholine receptors are the receptors on the edge of muscles that get the information from the brain to tell the muscles to contract. 46 00:05:35,110 --> 00:05:42,850 And they're sited at a particular site, a junction or a sign ups called the neuromuscular junction. 47 00:05:42,850 --> 00:05:50,920 So my first jobs with John, Seumas and Davis was to continue cloning the human receptors. 48 00:05:50,920 --> 00:05:59,110 From then, what I went on to find was that having actually isolated the C DNA is for the human receptors. 49 00:05:59,110 --> 00:06:10,480 We found, in fact, that there were a number of patients with myasthenia who actually had genetic cause of their disorders. 50 00:06:10,480 --> 00:06:14,940 And so the characteristic of myasthenia is fatigue. 51 00:06:14,940 --> 00:06:22,780 Pable muscle weakness. And these patients were. 52 00:06:22,780 --> 00:06:30,340 Had that sort of fatigue or muscle weakness, but they had it from birth, rather of developing it later on in life, 53 00:06:30,340 --> 00:06:39,760 which is what happens for the more common autoimmune form of this disease, which is myasthenia gravis anyway, from first identifying these patients. 54 00:06:39,760 --> 00:06:49,990 This now has grown into identifying actually that it is a rare disease, but not as uncommon as we originally thought of it. 55 00:06:49,990 --> 00:06:56,410 So the work that we did was finding patients who had mutations in these genes. 56 00:06:56,410 --> 00:07:03,430 We then got commissioned by the highly specialised services of the NHS to provide a centre for 57 00:07:03,430 --> 00:07:11,740 the whole of the UK to both diagnose these patients and to provide a clinical service for them. 58 00:07:11,740 --> 00:07:17,470 We then went on to find the most appropriate treatment. 59 00:07:17,470 --> 00:07:23,710 And in the early 2000s or so, we found a lover. 60 00:07:23,710 --> 00:07:35,800 My laboratory found that there was a particular gene called Dock's Seven, which has quite a large number of the mutations in it. 61 00:07:35,800 --> 00:07:42,940 So it was quite a common cause of these inherited my cynic's syndromes. 62 00:07:42,940 --> 00:07:50,710 And what we noticed from these patients was that effort, RINN, or Salbutamol, 63 00:07:50,710 --> 00:07:57,310 which are treatments for asthma, in fact had a remarkable beneficial effect on these patients. 64 00:07:57,310 --> 00:08:03,580 And so we brought the patients in, tried them out on these drugs, which are beta two agonist, 65 00:08:03,580 --> 00:08:09,070 and we're able to show that they actually had a really long life transforming effect 66 00:08:09,070 --> 00:08:13,990 on them and that they were able to get after their wheelchairs and start walking, 67 00:08:13,990 --> 00:08:18,280 whereas before they've been really fairly severely disabled. 68 00:08:18,280 --> 00:08:26,800 So we've gone on to apply this are, as it were, repurposing of these asthma drugs to a number of these neuromuscular junction disorders. 69 00:08:26,800 --> 00:08:36,550 And in fact, have now a sort of spectrum of treatments for our patients that in most cases is really life transforming. 70 00:08:36,550 --> 00:08:40,780 So that's essentially at the present stage we are at. 71 00:08:40,780 --> 00:08:46,930 But clearly, it is helpful for them, but it doesn't cure them. 72 00:08:46,930 --> 00:08:56,440 So I suppose the next stages of this whole, as it were, service that we provide and it is a national service, 73 00:08:56,440 --> 00:09:02,050 is to think about actually improving these therapies and what's going on at the moment. 74 00:09:02,050 --> 00:09:09,760 Very much is the idea that actually gene therapies for muscle diseases are a possibility. 75 00:09:09,760 --> 00:09:21,020 And therefore, our laboratory is looking closely at the ways in which we could go about applying gene therapy to genetic disorders. 76 00:09:21,020 --> 00:09:28,040 Is that gene therapy is broadly or most specifically in relation to neuromuscular disorders? 77 00:09:28,040 --> 00:09:35,800 Presumably this sort of great relation analogy between different different areas of therapy that inform each other. 78 00:09:35,800 --> 00:09:39,500 Is that the case? Yes, I think that's absolutely the case. 79 00:09:39,500 --> 00:09:48,890 I think in the past, muscle diseases have been always been really a poor relation because in fact, there haven't been many treatments for them. 80 00:09:48,890 --> 00:10:00,740 And many of them have been either lethal or really the idea is there's nothing you can do for for the patients. 81 00:10:00,740 --> 00:10:04,520 In theory, a bit like cystic fibrosis. 82 00:10:04,520 --> 00:10:13,280 And perhaps, you know, there've been modest improvements in the treatment of muscle diseases such as cystic fibrosis as well. 83 00:10:13,280 --> 00:10:17,210 But now suddenly these genetic diseases, 84 00:10:17,210 --> 00:10:27,470 people and pharma companies can see the actual possibility of really treating these patients and providing a potential inverted commas cure for them. 85 00:10:27,470 --> 00:10:30,980 Obviously, that's not quite as simple as that. 86 00:10:30,980 --> 00:10:40,910 But there is that potential. And so with the muscle diseases, suddenly they've got a whole number of rare diseases that also causes problems. 87 00:10:40,910 --> 00:10:49,310 But you can provide the same principle of gene therapy to all these different rare diseases with the potential of treatment. 88 00:10:49,310 --> 00:10:56,780 There obviously for each individual, it's still considered was the pharma companies still think it's a worthwhile 89 00:10:56,780 --> 00:11:03,500 investment only if they charge a fairly significant sum for treating each patient. 90 00:11:03,500 --> 00:11:15,080 But with respect to the muscle diseases, one's really looking at the delivery through adenovirus vectors and that sort of delivery platform 91 00:11:15,080 --> 00:11:21,320 that can be used for a whole series of different rare diseases using essentially the base, 92 00:11:21,320 --> 00:11:27,530 basically the same methodology, and therefore it becomes a possibility for rare diseases. 93 00:11:27,530 --> 00:11:35,620 So clearly, there's a lot of work into the future and a great future for what you're doing. 94 00:11:35,620 --> 00:11:41,030 Are there other other things on the horizon for you? I'm not really. 95 00:11:41,030 --> 00:11:51,980 I think, you know, the gene therapy. I'm looking for putting that into practise over the next sort of five year timeframe in 96 00:11:51,980 --> 00:11:59,120 that we're at the present looking at how we set up clinical trials for these therapies. 97 00:11:59,120 --> 00:12:06,050 And so hopefully within three to four years, the first patients would be going into the clinical trials. 98 00:12:06,050 --> 00:12:15,950 And then obviously, clinical trials take a few years to come to fruition to get the results and obviously then to take it into clinic. 99 00:12:15,950 --> 00:12:22,850 And actually, by that time, I feel my scientific career will have been done through its full circle. 100 00:12:22,850 --> 00:12:32,420 And it will be time for me to hang up my hang up my boots and retire into the distance. 101 00:12:32,420 --> 00:12:37,921 David, recent, thank you so much. Thank you.