1
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So could you just start by saying your name and your title and affiliation?

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I'm Alan Townsend, and I'm Professor.

3
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My official title is Professor of Molecular Immunology, although I was an honorary consultant physician here too for a long time.

4
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Um, and, uh, I work in the Weatherall Institute.

5
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I've been here since 1989, came to Oxford in 1983, literally in the Department of Surgery with Peter Morris.

6
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Yeah. So with that, my next question is. Without telling me your entire life story.

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Yeah. Could you just starting from when you first got interested in medicine?

8
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Yes. The two main stages of your career up till now.

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Yes. So I was at St Mary's Hospital Medical School and, uh, I had had very good teaching at my high school and in biology and chemistry and so on.

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I knew I wanted to be a doctor from the age of about 17, I suppose. Um, and at Mary's I was really tremendously inspired by Professor Stan appeared.

11
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He was a brilliant general physician.

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He'd got an FRC himself, um, for his work in the isolation of West and if I remember rightly, from, from the spleen and working with Sir Henry Dale.

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But he was an inspired teacher, a brilliant clinician.

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Patients adored him and a great teacher and demonstration at the bedside.

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And so I wanted to be like him, basically.

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So I, I, I loved clinical medicine, but I had become aware that science, you know, the science of medicine was extremely interesting.

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And in fact, there that little book taught by NAS Introduction to the Study of Experimental Medicine.

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So I try and get everybody to read. He comes to the lab. I got introduced to that not by Stan, actually, but by the professor of surgery.

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He was a very interesting character called Hugh Dudley, and I was editor of the Gazette and I asked him, amongst others, to write book reviews.

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So I wanted him to write a book review and a Little Book on Surgery by Zachary Cope.

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That was a great memories person in In Doggerel Verse.

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And Mr. Dudley did not have a tremendous sense of humour and he thought, this is a load of rubbish and he wouldn't dream of doing anything.

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So I sort of backed out of his office, but then he said, I will write you an essay on Claude Banana.

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So I thought, I wonder if that'll happen.

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Anyway, he wrote this fascinating essay about this book and about Claude Banal basically was pretty popular in popular.

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I mean, it was a biological it's popular in approach to science.

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And then and it's a fascinating account of his own research as well.

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And I was fascinated and I went to look for the book, eventually found it in the library,

29
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and later I met him and I thanked him for his article and he said,

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yes, took a little bit of effort because I couldn't find the original and I had to do it all from memory.

31
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And he'd quoted extensively, of course, he's that sort of chapter tremendous memory.

32
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So that book really inspired me.

33
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And I, you know, I talked about it a lot to Stan when we had time and stands.

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Ward rounds were extraordinary because we were reasonably busy, the London Teaching Hospital,

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but on the ward round we would discuss each patient with the patient, you know, fully involved, fascinated by the dicky bow.

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And we'd go through the management of the patient, given the information we had.

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But then he'd go on to what research was relevant and it just, you know,

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we'd get it seemed to me we'd get to the end of human knowledge and then we'd move onto the next patient.

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And so Waldron's did take a bit of time, but he was inspiring.

40
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So I wanted to do research and I went on after a bit of thinking,

41
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I ended up deciding to go to the National Institute for Medical Research to work with you to ask Anais and John Scahill on flu,

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because by that stage I'd got my ideas sorted out and I realised that immunology was a very much under-researched thing,

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that there were massive new tools coming in pre molecular biology, but there was the cell sorter,

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there was cloning, there was cloning of cells and monoclonal antibodies had arrived.

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And it struck me that these were very powerful tools to investigate horrible

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diseases like M.S. and and as viruses seem to be likely to be involved in mice,

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and the MHC was beginning to be understood, not understood, but at least was being studied.

48
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An MHC restriction had just been discovered. That's how T cells need two components to recognise an infected cell, the self and the virus.

49
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And this could be studied with flu better than any other virus because Mel Hill

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ran the W.H.O. surveillance of flu had done from right from the beginning.

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And John Scahill ran that. And they had every flu virus that had ever been isolated from humans in their freezer.

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So you had all these fantastic tools and to extraordinary people.

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So John Cahill, brilliant virologist and structural in a person as well,

54
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and an eater who was a really top immunologist and I was supervised by the two of them.

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And before we go any further, I think we should just do a kind of immunology.

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One, two, one, one, two, one. Yes. You don't know anything about the.

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Yes. Okay. So well, I lo I'm called an immunologist.

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I don't really regard myself as an immunologist. I see myself a little bit as an amateur immunologist.

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But, you know, I'm a generalist really, and interested in the biochemistry.

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But immunology is obviously the way the body defends itself against infections, against foreign invaders.

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And in my view, I think, you know, we evolve our immune systems in vertebrates have evolved to deal mainly with infections.

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I mean, some people think that the cancer is involved for a variety of reasons.

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I think that's very unlikely. But, um, but so we're being bombarded.

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With viruses and bacteria all the time, and yet we don't die from it most of the time.

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And that's because our immune system is able to protect us. And the vertebrate immune system is particularly interesting because it's adaptive.

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So it's not just general mechanisms which apply, you know, a set of general mechanisms which apply to everything.

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It actually adapts its response to suit the bug that's coming in.

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So with, you know, COVID, just like any other virus, you make T cells and antibodies, t cells of the white blood cells and develop in the thymus.

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That's what they call T for thymus and the antibodies which are produced by B cells and Basler Fabricius I won't go into all that,

70
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but the original discovery of them was in the birds in this thing called the Bursa and B cells,

71
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and these combinations,

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the antibodies are soluble proteins that are in your blood and in your extracellular fluid surrounding all the cells in your body that can get there.

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And t cells are these cells which clamber through out of your blood and come through the tissues looking for trouble, as it were.

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And if a t cell finds an infected so of your body, it'll kill it, destroy it,

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and that will get rid of the virus and or prevent the cell making more viruses and the antibodies do lots of different things.

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But probably the main thing they do, or the thing we understand best is they bind to the virus and prevent it getting into your cells.

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There are lots of other things they can do, but to me that's the most easily comprehensible.

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That's very helpful. Thank you. Yeah. So anyway, John and Ito have been very knowledgeable about all of this.

79
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And the big question at the time was, what do T cells see?

80
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What do they recognise? Because it was clear they recognised something specific.

81
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So they recognised in a virus infected cell but they didn't recognise that influenza B virus infected cell.

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What was it about the cell, the infected cells they recognised and we knew by that stage from, from Dr. and Zinckernagel.

83
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These are two people who won the Nobel Prize in 95 I think it was.

84
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But the key observations in 1974 were that the that the bits of you that vary between individuals that make tissue transplantation so difficult.

85
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The real role of those proteins is not to thwart the transplant surgeon, but to help you recognise infected cells.

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And so it was known that the T cells needed a component that's called the major histocompatibility,

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complex, horrible words, but a bit of you that varies between individuals and something from the virus.

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But how these got together, nobody knew.

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And it was very it seemed to me very important because there were lots of horrible diseases like M.S, for instance,

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or Ankylosing Spondylitis, etc., where those diseases occur much more frequently in people with particular tissue types.

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And so if we really understood how T cells worked, maybe we could have insight into all those diseases.

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So and I thought, right, that's it. That's a really, you know, that's what I want to do.

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So and those diseases are appeared to be an overreaction.

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And to be honest, is that wrong? Well, to be honest, I mean,

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there is some evidence that recently there's been a lot of excitement because

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there's a statistical association between Epstein-Barr virus infection and mice.

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But the causal relationship,

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I'm still it's very difficult to understand because the vast majority of people who get Epstein-Barr virus don't get them.

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And so and there are similar things going on with ankylosing spondylitis,

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but one of the things that's always troubled me is that we know very well how t cells work now, but we still don't understand these diseases.

101
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Not really. So they are attacking the cells?

102
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They are, yes. And that probably t cells involved. Certainly they're involved in mice with at closing.

103
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Still not absolutely clear to me anyway, but I'm a bit, you know, a bit of a donkey with these things because,

104
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you know, things come in and out of fashion, views come in and out of fashion.

105
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But the evidence isn't always 100% clear anyway.

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So but that's what I want to do. And at the time we had these different viruses, but we didn't have molecular biology,

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so we couldn't take one gene at a time and express them in cells.

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It's the obvious thing to do. Couldn't do it, but there were techniques for distinguishing the the eight RNA segments which are in a flu virus.

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They vary between viruses and some nice work from the states and at the Mount Sinai had been done to show that you could run these you could take pure

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virus and run it out on a Polyacrylamide gel just separates the RNA segments and they move slightly differently depending on where they come from.

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So if you have a virus that has two parents and you cross the parents and you get lots of little viruses, as it were, you can.

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Tell which gene came from which parent. So that gave us a pretty strong tool and basically took a very long time and a series of lucky breaks.

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So then there was this big chemical question how does a protein that's in the nucleus get recognised at the cell surface?

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And initially I had a bit of trouble with that because some very senior people said That can't be right, you know.

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But and this is where I think technology is so important that if you really know your technology and if it's as solid as a rock,

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they can repeat the experiment. And it's not difficult.

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You don't need special skills. And so eventually the the the big boss, Rolf Singh and Al Gore basically repeated the experiment and or did repeat it.

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So I sent him all the kit to do it. And then he said, Yeah, I believe you, you know.

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At the time he was a bit doubtful, which is fair enough and fair enough.

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So then. And as a student, you know, being doubted by such a senior person was a very testing experience.

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But it didn't last long. And once it was over, he was very supportive and always very kind.

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So. And so the T cell couldn't possibly recognise something that was in the nucleus because that's kind of buried behind.

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It's buried behind the membrane. So how did it. Now, of course, these things are always more complicated.

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So there were people who claimed that the nuclear protein was detectable at the cell surface.

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So what was the problem? But biochemically, that didn't make sense because.

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It was known by that time that a protein which gets to the cell surface and is inserted

127
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in the membrane of the cell surface has certain signals that direct it there.

128
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So particularly the thing called the signal sequence at the front, which pushes it into a part of the so called endoplasmic reticulum,

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which is topographically external, and then it moves up to the surface.

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Now cells without that shouldn't be at the cell surface, you know, unless there's some other mechanism for proteins without that.

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I think you said cells without that. But you mean proteins? Proteins without that sort of.

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Yes, proteins without that signal sequence. So.

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But by that stage, molecular biology had arrived and we had cDNA DNA copies and we could express these in the expression vector.

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So you could put genes one at a time into cells. And we did that.

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And the nuclear protein was all it was required, didn't require anything else.

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So had these cells that had just expressed nuclear protein, you could stain it in the nucleus, couldn't stand it on the cell surface.

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And they were recognised very, very strongly by the T cells.

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And I tried to publish that and I got a barrage of abuse from the referee saying this is impossible.

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I said, Well, that's the data, it's possible. And then, you know, so but then, you know,

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it had lots more controls and we had t cells that recognise the nuclear produced from from different viruses and so forth.

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And that eventually was published in a set of papers.

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And I then moved on to just asking very simple question what if there isn't a signal sequence that we can see,

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maybe there's some hidden signal sequence or something. So a friend of mine was working on the movement of that protein into the nucleus,

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and he had chopped up the gene and expressed different bits and showed that there was a signal which took it into the nucleus.

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So I said, Well, could I use the bits? And we'll just see what happens. The recognition surface.

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And the other thing that was very obvious when the biochemistry, these bits which don't fold fully,

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were degraded very rapidly in the cell and in some cases I couldn't detect them at all.

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That also gave a big problem to the referees, as if you can't detect the protein.

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Where is it?

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But it said it was clear they were being degraded rapidly in the cytosol, in the cytoplasm and something that's been recognised at the surface.

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And by that stage it was known that so-called class two restricted cells,

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cells that recognise proteins that come into a cell from outside of degraded in vesicle.

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So they remain topically, topographically external and they bind into a different MHC molecule and those are recognised by T cell.

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So they were all sharing the same V genes that the gene pool which goes to make up the receptors are all come from the same pool.

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So they must be recognising a peptide. It's just it's coming from inside.

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And that took 14 years basically to go through all the bits and pieces and lots of other people, of course joined in.

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But it turns out there is a special mechanism in the cell.

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Proteins are degraded that transported by a different transporter into the endoplasmic reticulum where they bind to the MHC molecule that goes up.

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That complex is then recognised by the T cell receptor. And so there are lots of nuances to that.

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Many, many different people have contributed to that. That all arose from my in a Ph.D. and that was all very interesting.

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But at the end of that, really, once we got to that stage,

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I didn't feel particularly qualified to go into the minutia of the biochemistry or the minutia of the structures.

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You know, the lots of people doing structures of MHC molecules with different peptides or T cell receptors and so on.

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And I really wanted to go back and practice medicine. I hadn't done it for a long time, so I went back.

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I kept things going in the lab of various projects, but in 1994 I went back and retrained myself.

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I did four years of retraining, but two years as a chair.

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And then I was a registrar and I worked with as many consultant as I could here.

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They're all very good here. So you came to what I was in? Yeah, I came, doctor, in 1983, right?

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To finish my day filled with Andrew. Michael to do to try and apply it to humans, which we did.

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And then and so I then just went back to being a general, basically a general physician,

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and I decided to work with the geriatricians because they are the best general physicians.

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And how James and Simon Winnow were absolutely superb general physicians.

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So I, I did my registrar work with them for two years and then they invited me to join them as a consultant on their firm.

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So I did that for the next six years very happily, and I was doing basically half time.

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So I it ended up being more than half time because I was doing outpatient clinics when I wasn't on the beds, but I was very busy.

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I was keeping the lab ticking, very happy to the lab was here as well by then.

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Yeah. So yeah but the head of the MRC was being a bit he said he wasn't being critical and he

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said he felt it was a wonderful thing that I was going back and practising medicine again,

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but it didn't come across like that and I'm like, you know, I had a program grant and but you know,

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it was probably a bit doubtful about whether that would get renewed.

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And, and because we were beginning to do a bit of work on cancer,

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dying of colon cancer because it looked like colon cancer probably spewed out

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aberrant proteins that might get into the system and some things like that.

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But it's a bit before it's time to be honest. And again, it didn't it I mean, we did some work on it, but and then I then got cancer myself.

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So I was very ill for about a year and luckily it was cured.

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But then I thought, right now I'm going to do so.

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I just decided to Roma sleeves up get back into the lab and I European working director

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would come in which I hated because it completely changed our way of working where,

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you know, junior staff for sixes and sevens they had to have rotas which is still the same now,

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which all over the place they don't really have a firm structure.

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We worked with one firm, you know, I as junior doctor we'd you'd do six months with one firm more than one year.

192
00:20:28,450 --> 00:20:31,840
And I set my case, I, I did a year or two with them.

193
00:20:32,200 --> 00:20:37,630
And you really get to know your bosses, you know their strengths, occasional, very occasional weaknesses.

194
00:20:37,960 --> 00:20:45,610
And then you get to know everybody. And it's it's a very supportive environment when you're dashing,

195
00:20:45,880 --> 00:20:50,890
putting out fires for one firm in another because you're only allowed to work 40 hours.

196
00:20:51,160 --> 00:20:57,910
So you're never you know, I think psychologically that's far more stressful and and less of an educational experience.

197
00:20:57,910 --> 00:21:01,480
Actually, you may not be so tired, but probably stressed out anyway. My opinion.

198
00:21:02,790 --> 00:21:13,230
But so at the end of that and I've been ill and I talked about it how and people I decided to get back in the lab.

199
00:21:14,130 --> 00:21:17,520
So I started just working, doing things.

200
00:21:17,640 --> 00:21:28,910
And we've worked on various aspects of flu and developed a live attenuated flu virus that we would hope Monday will be a vaccine.

201
00:21:28,920 --> 00:21:33,659
It's very difficult to get funding, serious funding for that, and it works beautifully.

202
00:21:33,660 --> 00:21:38,400
And we've applied it in lots of different circumstances. We've collaborated people all over the world.

203
00:21:42,850 --> 00:21:48,820
But, uh, we haven't been able to to get it commercialised.

204
00:21:49,330 --> 00:21:55,389
But I'm interested in all aspects of immunology, you know, and I work, tend to work with students.

205
00:21:55,390 --> 00:22:02,890
So we had a very good student. We started when it became possible to isolate monoclonal antibodies from humans,

206
00:22:03,280 --> 00:22:08,410
we began to look at the monoclonal antibody response to flu, to what is a model of antibody.

207
00:22:09,490 --> 00:22:22,330
And Caesar, a Milstein and Akola in 1975 fused a B-cell in a normal lymphocyte with a malignant B cell.

208
00:22:23,080 --> 00:22:26,620
And this sort of experiment been done a lot by other people.

209
00:22:26,830 --> 00:22:36,430
But it always turned out that the normal genes seemed to suppress the tumour genes and not much happened in this case.

210
00:22:37,210 --> 00:22:46,480
They got the growth properties of the tumour, so it grew in tissue culture and it carried on producing antibodies from the original B-cell.

211
00:22:47,440 --> 00:22:50,530
And because these grow very well, they'll grow a single clone.

212
00:22:50,530 --> 00:22:53,440
So you end up with an absolutely pure single antibody.

213
00:22:54,100 --> 00:23:03,070
And there's a classic paper that they wrote in 1975 in which in typical beautiful understatement, there's one sentence at the bottom which says,

214
00:23:03,400 --> 00:23:09,280
We understand this may have commercial implications or something of that kind or, you know, may have many applications.

215
00:23:09,940 --> 00:23:13,930
And Margaret Thatcher got very cross with them because they didn't patent it all.

216
00:23:14,170 --> 00:23:18,370
And a lot of patents then went to the States and there was a huge hoo ha about it

217
00:23:18,760 --> 00:23:23,620
and lots of people made lots of money which really should have been done in Britain.

218
00:23:23,620 --> 00:23:30,370
But anyway, but that's always been, I think one of the traditions that I actually secretly greatly admire is that

219
00:23:30,550 --> 00:23:36,190
we talk to people about stuff and that's why things interesting things happen.

220
00:23:36,340 --> 00:23:43,809
And if we didn't talk to people, they wouldn't be interesting things. And I think the university here at the moment has lost its way a bit on this.

221
00:23:43,810 --> 00:23:48,760
We're just obsessed with patenting everything and spin offs and all the rest of it.

222
00:23:48,760 --> 00:23:54,790
And personally I think it's danger in that anyway to carry on with the monitor.

223
00:23:54,800 --> 00:24:00,970
And so we're very interested in looking at the monoclonal response to flu because you might, you know, begin to dissect interesting things.

224
00:24:02,140 --> 00:24:11,560
And one of my students actually, he wasn't my student, but he worked with us quite a lot and collaborating with us went back to Taiwan,

225
00:24:12,100 --> 00:24:19,600
Arthur Fung and he's now a consultant in childhood infectious diseases there.

226
00:24:19,600 --> 00:24:26,620
But he carried on with becoming very good at isolating monoclonal antibody against a variety of different infections.

227
00:24:26,620 --> 00:24:31,320
And so we've been working with him on COVID because he's done a lot of isolations.

228
00:24:32,210 --> 00:24:33,010
You don't get that.

229
00:24:33,130 --> 00:24:42,850
So, so, so one of the things it's been a great pleasure in my career is the collaborations because I like working with a small group I've never been.

230
00:24:42,850 --> 00:24:51,190
I tried to expand at one point and I just didn't. I'd much rather work with a small group of well-integrated people and then collaborate.

231
00:24:51,580 --> 00:25:00,280
And we collaborate very widely all over the world with various groups who I've known for a long time, you know, and with students.

232
00:25:00,280 --> 00:25:06,399
And it's it's very pleasurable, you know, and nine times out of ten, it works really well.

233
00:25:06,400 --> 00:25:12,190
And you have a very open you can have very open discussion about things.

234
00:25:12,190 --> 00:25:17,110
And so that's been that's been great fun and we've been very busy doing that over the last few years.

235
00:25:17,920 --> 00:25:21,310
So and that was all moving forward.

236
00:25:22,000 --> 00:25:27,000
And then a few years ago I met Mark Howarth, who I mentioned earlier.

237
00:25:27,040 --> 00:25:34,809
Now, Mark, I have a short list of people I've met over the years who I think might be in the running for a Nobel Prize.

238
00:25:34,810 --> 00:25:45,640
And he's one of them. I mean, I think he has a his work has this special quality of being fundamental in terms of fundamental insights into biology,

239
00:25:46,030 --> 00:25:49,120
while also having wonderful applications that you can pick out of them.

240
00:25:49,270 --> 00:25:53,049
And so I and I'm not familiar with all of his work,

241
00:25:53,050 --> 00:26:06,129
but I was actually can I read a review that he'd written about an enzyme that we use a lot for putting biotin groups onto proteins and we're lazy.

242
00:26:06,130 --> 00:26:13,300
And so we were buying a kit from the States and this blooming kit kept on getting impounded at Stansted.

243
00:26:13,300 --> 00:26:17,560
And by the time it arrived at us, the enzyme was dead and very expensive.

244
00:26:18,070 --> 00:26:24,820
So I was looking around either about thinking about making our own or anyone who was any good at making it in the university.

245
00:26:24,820 --> 00:26:30,250
And then I read a review by him about in how to make it and how best to do various aspects of it.

246
00:26:30,880 --> 00:26:35,800
So then I finished the review. I said, Where does he come from? He said, He's in chemistry in Oxford.

247
00:26:36,340 --> 00:26:41,650
So I called him up and said, Can I come scrounge some of this stuff? He said, Sure, I'll have breakfast with him.

248
00:26:41,860 --> 00:26:50,819
And then he told. About what he was now doing, which is this extraordinary piece of work he's done on understanding a particular

249
00:26:50,820 --> 00:26:56,790
chemical bond in a particular protein in the streptococcus pathogens organism.

250
00:26:56,790 --> 00:27:02,609
And it's a nasty bug which causes sore throats and it has all sorts of very unpleasant side effects.

251
00:27:02,610 --> 00:27:05,790
So rheumatic heart disease and joint disease and all sorts of things.

252
00:27:06,420 --> 00:27:13,770
And it's luckily it is sensitive to penicillin and this remains so, but it's a very unpleasant organism.

253
00:27:14,280 --> 00:27:20,280
And so there's a lot of work done there. And one of the things that I'm not sure he was the first person to ever observe this,

254
00:27:20,280 --> 00:27:28,319
but he picked up on is that there's a to one of the proteins which is a long chain which holds the on to your throat.

255
00:27:28,320 --> 00:27:33,330
Basically it's like an anchor and has to be strong from the bugs point of view.

256
00:27:33,660 --> 00:27:42,299
And is that the chain link is held together internally by a bond which is not a disulphide bond,

257
00:27:42,300 --> 00:27:51,090
not disulphide bonds are bonds which form within globular proteins to hold them together in eukaryotic cells in our types of cell.

258
00:27:51,450 --> 00:27:56,279
But bugs don't make those bonds, but they make now they use a peptide bond.

259
00:27:56,280 --> 00:27:59,879
Now normally in our cells, peptide bonds are only sequential.

260
00:27:59,880 --> 00:28:04,710
They're only between units in a long line, but not within or between chains.

261
00:28:05,280 --> 00:28:08,810
And this was a between chain peptide bond, which is very unusual.

262
00:28:09,360 --> 00:28:20,310
So he, being a very, very gifted biochemist, dissected it all and he found that he could take one bit of the protein out and leave the other bit.

263
00:28:20,610 --> 00:28:26,849
And basically when you mix them together, the peptide bond formed and it didn't require an external energy source.

264
00:28:26,850 --> 00:28:32,300
Normally, you know, you need an enzyme and a bit of ATP and double blind would be very commonly known, a bit of it.

265
00:28:32,310 --> 00:28:38,370
The energy required was all encased as it were, in the sort of spring of one half.

266
00:28:38,950 --> 00:28:45,240
And he realised that this was quite a nice way of sticking proteins together that you might want to stick together.

267
00:28:46,350 --> 00:28:57,150
Meanwhile, immunologists had been very much aware that particular antigens, antigens that are particles like viruses,

268
00:28:57,420 --> 00:29:03,060
are much more powerful at stimulating the immune system than just soluble proteins.

269
00:29:03,540 --> 00:29:10,919
And of course, this has implications for vaccines. And and of course, it's kind of obvious because that's what we have to defend against.

270
00:29:10,920 --> 00:29:17,579
So and various clever people in the world had been looking at manmade particles,

271
00:29:17,580 --> 00:29:23,200
as it were, that might be useful for this purpose as scaffolds and fantastic.

272
00:29:23,540 --> 00:29:27,030
And this person David Baker in.

273
00:29:28,450 --> 00:29:33,460
Wisconsin. I think the Wisconsin legacy and Washington.

274
00:29:33,580 --> 00:29:37,290
Yeah. Uh, I think it's Washington. You have to check that.

275
00:29:38,510 --> 00:29:44,730
Anyway, he is another person is on my short list, actually, as a structural biologist.

276
00:29:45,270 --> 00:29:51,409
And he. Takes proteins that have the capacity for being a subunit.

277
00:29:51,410 --> 00:29:53,420
Usually that might be trimeric I say,

278
00:29:53,420 --> 00:30:03,620
and it looks a bit like a pyramid and then fiddles with the three ends and get some stick together and they assemble really beautiful work.

279
00:30:04,190 --> 00:30:16,219
He's done a lot of that and he came up with one particular one, which is an enzyme from a bug in the Deep Sea Events course at Toga Maritime.

280
00:30:16,220 --> 00:30:26,150
And I think it is that an enzyme that's involved in sugar metabolism in that organism, but it does a reaction which isn't, doesn't happen in us.

281
00:30:26,180 --> 00:30:32,809
So um, uh, he, he got this to assemble and it's basically a trimer.

282
00:30:32,810 --> 00:30:35,210
So it's three stuck together in a pyramid shape.

283
00:30:35,720 --> 00:30:44,180
And when they assemble, they form a perfect dodecahedron turducken, a 12 sided figure with each side being a pantomime, a perfect pantomime.

284
00:30:44,600 --> 00:30:48,620
Well, I think they're perfect Benjamins. And of course, this is Euclidean.

285
00:30:48,620 --> 00:30:48,979
I mean,

286
00:30:48,980 --> 00:30:57,440
this is in book 13 of Euclid the present they they do dictionaries described it has various extremely interesting properties in terms it's got the

287
00:30:57,440 --> 00:31:10,909
golden ratio all over it it's got it's a it's got packing maxima so you can pack more into that space than in any of the other figures in in Euclid,

288
00:31:10,910 --> 00:31:15,260
as I understand it. So it's better. It's it it's packing.

289
00:31:15,410 --> 00:31:21,890
It can pack really effectively. And it has because it each of these is a trimer.

290
00:31:22,500 --> 00:31:30,830
It ends up with 12 containers, 20 APC's and each apex has got three of these things in it.

291
00:31:31,490 --> 00:31:38,660
So he's stuck what that so and he showed that you could put fluorescent proteins at either end of the

292
00:31:38,660 --> 00:31:42,920
trimer and the thing would still assemble so you can make these very very fluorescent particles.

293
00:31:44,180 --> 00:31:51,770
Spotted that and realised that he could put the catcher part one half of this bit of protein on one of

294
00:31:51,770 --> 00:31:57,320
the ends and then you have a particle and if you put the tag the other bit on any protein you wanted,

295
00:31:57,560 --> 00:32:05,480
then you could just stick them together and all the difficulties of making specific particles would be solved in one simple, very simple thing.

296
00:32:06,110 --> 00:32:14,270
So he did that and it worked. It's you can assemble proteins onto this particle by just sticking the SPI tag.

297
00:32:14,420 --> 00:32:20,840
He calls it spy catcher and spy tag spies because of step by origin is we've been asked not to use the

298
00:32:20,840 --> 00:32:27,319
word spy because of worries about conspiracy theorists and the government spying on us through vaccines,

299
00:32:27,320 --> 00:32:31,820
all that sort of nonsense. But, uh, so that worked.

300
00:32:32,330 --> 00:32:37,310
And he told me all about this. This breakfast. Oh, you know, it's absolutely amazing.

301
00:32:37,700 --> 00:32:41,480
And he wasn't studying flu, so I said, Well, should we study flu together?

302
00:32:41,930 --> 00:32:47,420
Because more complicated with flu, because the two key proteins haemagglutinin,

303
00:32:47,810 --> 00:32:54,200
it has got three units stuck together and the the other key protein and it's got four units stuck together.

304
00:32:54,950 --> 00:33:00,500
Now the ends of these three are all I'm just going to say that will slowly for the benefit of the transcribed neuraminidase.

305
00:33:00,530 --> 00:33:09,980
Neuraminidase is an enzyme that's on the surface of the flu virus, which actually a flu virus binds to a sugar called sialic acid.

306
00:33:10,460 --> 00:33:17,090
And uh, in order to be released from an infected cell, that has to be chopped, and that's chopped by the near minute.

307
00:33:17,960 --> 00:33:28,280
So the names are a little bit crazy because but we're very bad at names in science and so and so.

308
00:33:28,460 --> 00:33:32,330
But these are both important proteins for flu because if you make antibodies to them,

309
00:33:32,570 --> 00:33:38,059
those antibodies can be protective and they either prevent the virus getting out if they block in your amenities

310
00:33:38,060 --> 00:33:43,460
action or they prevent the virus getting in by stopping the haemagglutinin from binding to acidic acid.

311
00:33:43,820 --> 00:33:53,000
And that's quite apart from what T cells do. And antibodies of course can actually prevent the infection ever getting into you,

312
00:33:53,330 --> 00:33:58,399
which is better than even the T-cell because the T cell only kills cells once they've been infected.

313
00:33:58,400 --> 00:34:01,670
So so I was very interested to see what would happen.

314
00:34:02,030 --> 00:34:08,149
And my worry was that if you have a protein with three of the SPI tags on it and you've

315
00:34:08,150 --> 00:34:13,220
got a particle with 60 places for it to bind and another particle next door with 60.

316
00:34:13,460 --> 00:34:17,030
But instead of binding to this particle, it might bind to that part.

317
00:34:17,120 --> 00:34:21,800
And then you might end up with a lattice which would just come out of solution

318
00:34:22,010 --> 00:34:25,880
and that would make a mess and might be very difficult to use a vaccine.

319
00:34:26,480 --> 00:34:31,310
So we did a whole lot of experiments together over a couple of years with him in Germany,

320
00:34:31,550 --> 00:34:37,820
and then he came up with a whole set of other proteins that had multiple attachment sites for the spy tag.

321
00:34:38,360 --> 00:34:47,270
And basically the nice thing is that actually it works fine as long as the three sites are close together, they prefer to bind to one particle.

322
00:34:47,310 --> 00:34:49,860
You do get a little bit of cross-linking, but very little.

323
00:34:50,100 --> 00:34:56,850
And the only time you really get crossing is if they're sticking out at either end of a, you know, a dime or two things stuck together.

324
00:34:57,030 --> 00:35:01,770
And then you did get a lattice forming. So that was a very technical paper.

325
00:35:02,130 --> 00:35:12,390
And and we published it and that gave us all the technology we needed to now do things properly or not properly.

326
00:35:12,390 --> 00:35:17,670
And we did it very properly in that paper, but to actually do things in a a applied way for a particular thing.

327
00:35:17,670 --> 00:35:20,370
So we were working on flu and the flu.

328
00:35:20,580 --> 00:35:27,450
We're particularly interested in the neuraminidase because modern flu vaccines don't really have much neuraminidase or it's very,

329
00:35:27,450 --> 00:35:30,629
very amount it's not regulated against.

330
00:35:30,630 --> 00:35:35,910
And yet we now know from really excellent evidence that if we had a good antibody to neuraminidase,

331
00:35:36,810 --> 00:35:40,860
that would add to the protection of the flu vaccine, which, as you know, is not very good.

332
00:35:40,860 --> 00:35:48,509
It averages about 50%. It can be worse or a bit better. But if we really had good neuraminidase antibody, that might bump it up, you know,

333
00:35:48,510 --> 00:35:52,650
to regularly more like 60, 70%, which would be a really valuable thing.

334
00:36:33,300 --> 00:36:39,450
And the important thing about the particle, because it's been known for many years that if you immunise the neuraminidase protein,

335
00:36:39,450 --> 00:36:44,310
you can get some protection, but the particle makes it more powerful, so you need less of it.

336
00:36:44,320 --> 00:36:50,580
So if you've got a problem with production and you know, you may be able to use ten times less to get an effective vaccine.

337
00:36:50,580 --> 00:36:55,760
So that's the benefit. And in terms of its transport ability and use.

338
00:36:56,190 --> 00:36:59,510
Yes. Now for neuraminidase, pneumonia is a complex protein.

339
00:36:59,520 --> 00:37:05,090
So as we come on to the covered version, the COVID version, you can freeze dry it like coffee powder.

340
00:37:05,520 --> 00:37:11,280
But we haven't tried that when you're Amanda, is that that's a big ask because it's a very complicated protein.

341
00:37:11,280 --> 00:37:15,419
And if you freeze dried it, I have a feeling you might end up with something.

342
00:37:15,420 --> 00:37:22,020
It wasn't active anymore, but we will do that. It's part of the project, but you don't have to keep it in an 80 -80 fridge, all that kind of.

343
00:37:22,320 --> 00:37:26,910
Well, we keep everything in -80 fridge until we know that we don't need to.

344
00:37:26,940 --> 00:37:30,070
So at the moment, it's all in the mind. Ten -83. Yeah.

345
00:37:30,120 --> 00:37:34,500
Okay, so let's, let's get onto it. So I'm asking everybody this.

346
00:37:35,070 --> 00:37:41,879
Can you remember where you were when you first heard that the looked as if there was a pandemic developing?

347
00:37:41,880 --> 00:37:47,070
And how soon after that you thought that was something that you and your colleagues might jump into?

348
00:37:48,570 --> 00:38:00,000
I think we were here in the lab chatting and it became obvious that there was and I mean, we had a sort of a very early warning because,

349
00:38:00,240 --> 00:38:07,740
you know, the institute has a long running collaboration with China, which David Weatherall set up many, many 30 years ago.

350
00:38:08,310 --> 00:38:10,410
And it's been incredibly productive.

351
00:38:10,920 --> 00:38:18,660
Uh, we, we've had many, many Chinese students have been very successful, including George GAO, who's now, you know,

352
00:38:19,410 --> 00:38:28,500
very senior in the scientific administration in China, who is a brilliant scientist, structural biologist and and virologist.

353
00:38:29,070 --> 00:38:35,280
So and I'm I'm very fond of George and whenever possible, I mean, he's incredibly busy now.

354
00:38:35,280 --> 00:38:39,330
We talk and we've done some collaborative work together on flu on their many days actually.

355
00:38:40,320 --> 00:38:46,740
So we had warning because he basically told us that things were not looking good and that

356
00:38:46,740 --> 00:38:53,010
was about the time that the first sequences were published and doing something like that.

357
00:38:53,220 --> 00:38:56,070
Yes. And a structure was well,

358
00:38:56,070 --> 00:39:02,190
we already knew the structure of the Salisbury related cells protein and we're pretty certain that this would be very similar.

359
00:39:02,310 --> 00:39:07,170
And I think a structure came out very soon afterwards and very clearly very similar.

360
00:39:07,170 --> 00:39:12,540
And it's a trimer, um, the flu, the virus is an RNA virus.

361
00:39:12,540 --> 00:39:21,090
So it's, you know, in a sense not so dissimilar. Well, it's very dissimilar to flu, but it's, it, it's of that family of RNA viruses.

362
00:39:21,510 --> 00:39:26,430
It, um, uh, its surface protein is a trimer, as you would expect.

363
00:39:27,030 --> 00:39:32,549
Uh, it was highly suspected that antibodies to that protein would probably be protective.

364
00:39:32,550 --> 00:39:37,950
It wasn't. I mean, obviously at that stage we didn't know and we didn't know what the receptor was at that stage.

365
00:39:38,490 --> 00:39:40,210
Um, but uh,

366
00:39:41,040 --> 00:39:50,610
what was known is that from SA's you could extrapolate and from SA's it was known that the there was a thing called the receptor binding domain,

367
00:39:51,330 --> 00:39:57,510
um, which forms in our minds it forms a kind of a squirrel shaped.

368
00:39:58,460 --> 00:40:04,880
Blob mannequins. I would look out of my window watching the squirrels eating my bird feed, which was driving me up the wall.

369
00:40:04,880 --> 00:40:08,750
And they were sitting there looking at me and I thought, Gosh, that looks just like the IBD.

370
00:40:09,440 --> 00:40:16,040
So that helps us just remember the anatomy of the molecule and it was already known some very nice work.

371
00:40:16,490 --> 00:40:25,610
Peter Hotez is group and people surrounding him that you could that that unlike flu that receptor binding domain folded on its own.

372
00:40:25,700 --> 00:40:30,950
So you could you could express just that in in eukaryotic cells and it would

373
00:40:30,950 --> 00:40:35,540
fold bind the antibodies and work to the vaccine for cells in animal models.

374
00:40:35,870 --> 00:40:39,770
So we already knew that and we were very suspicious that the same would be true for this.

375
00:40:40,010 --> 00:40:44,030
So when the structure came out, there was something that looked exactly like the receptor binding domain.

376
00:40:44,450 --> 00:40:49,640
And I remember sitting here with Pramila and Jack and looking at it and saying, well, that's,

377
00:40:50,090 --> 00:40:54,700
you know, let's let's just make that and stick it on the particle and see what happens.

378
00:40:54,740 --> 00:40:59,209
So we were we immediately saw a way of doing this.

379
00:40:59,210 --> 00:41:03,980
We were a little bit making a bet because we didn't know what the receptor was at that stage.

380
00:41:03,980 --> 00:41:08,240
And we didn't really know that this was the receptor binding domain for this virus.

381
00:41:09,500 --> 00:41:16,610
But it was a reasonable, you know, assumption. So I'd have to look at my notebooks to find out exactly what day we actually got started on it.

382
00:41:16,610 --> 00:41:22,250
But we ordered the sequences and designed something where we put the spy tag at the front.

383
00:41:22,460 --> 00:41:28,150
I mostly put things at the end. I don't know why, but I've always rather like put them at the front.

384
00:41:28,160 --> 00:41:36,410
So we had the signal sequence smarter than we had the the receptor binding domain and then something to help purified at the end.

385
00:41:36,420 --> 00:41:40,610
And that was the first design and it just worked straight off. It expressed really well.

386
00:41:40,610 --> 00:41:45,980
I mean we were surprised at how well it expressed and it assembled on the particle perfectly.

387
00:41:46,400 --> 00:41:51,020
And it's a monomer, it's just one. So there's none of this problem of it possibly crosslinking this or that.

388
00:41:51,650 --> 00:42:04,790
And the particles were highly immunogenic and we showed that they were very, very stable so we could freeze dry it and then thaw it.

389
00:42:04,790 --> 00:42:08,210
And it was just as good. So there's no turning for cold chain.

390
00:42:08,240 --> 00:42:16,729
You can just send it through the post. And in fact, when we tried to get various people to help us with an animal model and we

391
00:42:16,730 --> 00:42:21,050
couldn't get it in in England and the only animal models were at Porton Down.

392
00:42:21,350 --> 00:42:25,100
It's huge long queue and very expensive.

393
00:42:25,100 --> 00:42:32,270
I mean, horrific, expensive. And we weren't getting any funding, so we had a little bit of funding from the University Fund,

394
00:42:32,270 --> 00:42:36,470
but it wasn't enough to cover that which was going to require £400,000 or something.

395
00:42:37,100 --> 00:42:46,639
So I did what I usually do in these circumstances. I rang my mates in America because every few years I go to NIH and I talk to the vaccine group.

396
00:42:46,640 --> 00:42:49,020
They're just not by invitation.

397
00:42:49,040 --> 00:42:55,220
I kind of thrust myself upon them, as it were, because they're always enthusiastic and you always get a fantastic discussion.

398
00:42:55,250 --> 00:42:59,899
This is the National Institutes of Health. Yes. And I did so.

399
00:42:59,900 --> 00:43:03,559
I did the same through John. You know, he's an old friend.

400
00:43:03,560 --> 00:43:08,150
I said, you know, we'd love a bit of discussion. And he I'm not sure who he spoke to.

401
00:43:08,150 --> 00:43:16,250
But anyway, the next thing I knew, there was a panel discussion booked by Zoom with lots of fantastic people on it.

402
00:43:16,610 --> 00:43:23,750
And I just said what we were doing. And, you know, any advice and any help you can give us?

403
00:45:29,350 --> 00:45:34,060
So I just thought maybe this question ought to come up later, but it's the thing that immediately comes to mind.

404
00:45:35,140 --> 00:45:38,460
Clearly, all the vaccines were developed around the world. Yes.

405
00:45:38,470 --> 00:45:43,360
The money was poured into those. Yes. Why did you struggle to get funding for this?

406
00:45:43,390 --> 00:45:45,879
Was it just because it was a novel mechanism?

407
00:45:45,880 --> 00:45:55,120
Whereas I think you'll have to ask the UK either because I find everybody with an existing platform that already, I don't know, maybe I'm getting old.

408
00:45:55,180 --> 00:46:06,280
I don't know. But I did try and talk to everybody I could and I pointed out that this was very easy to match to any new any new variant.

409
00:46:06,820 --> 00:46:11,680
Very simple to make. You need very low doses, you know.

410
00:46:12,520 --> 00:46:13,940
But we just didn't get anywhere.

411
00:46:13,960 --> 00:46:22,690
I think the problem was that at that stage, there were a lot of people shouting their way, as, you know, advertising their wares.

412
00:46:23,140 --> 00:46:29,440
And Oxford, obviously, that Jenner were moving forward very rapidly with a very successful vaccine.

413
00:46:30,130 --> 00:46:38,110
And I think the attitude was, why would we want to spend a lot of money on an untested technology at this stage in the pandemic?

414
00:46:38,380 --> 00:46:44,170
And I can sort of understand that argument. It's very short sighted, but there we are.

415
00:46:44,820 --> 00:46:48,010
So we we persisted.

416
00:46:48,010 --> 00:46:53,120
And the the next step was to make it cheap and quick.

417
00:46:53,770 --> 00:46:59,650
So again and this is something I've always believed in, talk to people.

418
00:47:00,040 --> 00:47:04,060
Don't keep it quiet. You know, and we don't we haven't tried to patent any of this.

419
00:47:04,420 --> 00:47:07,690
So then and we haven't.

420
00:47:07,720 --> 00:47:14,260
I mean, some later down the line have. But so I, we work with absolute antibody quite a lot.

421
00:47:14,330 --> 00:47:24,250
Absolute antibody at that stage. Absolute antibody was founded by groups of excellent biochemists from Oxford who patchy Oxford but

422
00:47:24,430 --> 00:47:31,750
a bit fed up with Oxford administration and formed their own little company to make antibodies.

423
00:47:32,140 --> 00:47:35,950
And they've been very successful because they're very high quality and their quality control is good.

424
00:47:35,960 --> 00:47:39,700
So when we wanted a lot of the particular antibody, we'd ask them or other things.

425
00:47:39,940 --> 00:47:46,630
And at that time we were also working on producing a very simple test for antibodies to COVID.

426
00:47:47,670 --> 00:47:53,410
And that's another story. But it's one I'd like to tell. It's quite nice. And they were making the reagent for us.

427
00:47:53,770 --> 00:48:00,120
And in Wilkinson, who was the senior scientist there, I was telling him what we're doing and what when,

428
00:48:00,340 --> 00:48:03,040
because sometimes if you explain what you're going to use it for,

429
00:48:03,190 --> 00:48:07,060
they can give you a very good advice about what level of purity you ought to go for and so on.

430
00:48:07,360 --> 00:48:14,470
So I was talking to him about it and they explained it to me and what's really interesting and talked about the particle and everything else.

431
00:48:15,310 --> 00:48:25,690
The next thing I know, I get this call from a chap from the CPI and Chris Oh, this will be terribly embarrassing.

432
00:48:25,690 --> 00:48:29,670
If I can't remember his surname, it'll come to me in a moment. I'm going see now.

433
00:48:29,680 --> 00:48:33,040
So CPI, the Centre for Process Innovation.

434
00:48:33,300 --> 00:48:34,870
Now I had never heard of them.

435
00:48:35,920 --> 00:48:46,870
They are funded by government funds mostly and their role is to have a very wide range of technologies, help people develop a technology to a product.

436
00:48:47,470 --> 00:48:52,360
So they help with they can investigate, scale up its complications of that.

437
00:48:53,050 --> 00:48:57,650
And I got this call from Chris. He said, I hear you.

438
00:48:57,740 --> 00:48:59,650
You're working on a COVID vaccine.

439
00:48:59,840 --> 00:49:07,210
And and because I'd said to Ian, you know, we'd really like to make it in yeast because that would be cheap and quick.

440
00:49:07,570 --> 00:49:11,170
And he said, I can put you in touch with people who work with yeast.

441
00:49:11,440 --> 00:49:15,250
So he put me in touch with in Will Ian Fotheringham,

442
00:49:15,790 --> 00:49:25,120
who is head of a company called Engender that are real specialists in yeast protein production, amongst other things.

443
00:49:25,750 --> 00:49:31,930
And he's a wonderful chap and I had an absolutely delightful conversation with him,

444
00:49:32,980 --> 00:49:40,390
the his his sort of senior post-doc and Chris and they said, Well, why don't we just try it?

445
00:49:41,200 --> 00:49:45,970
So then Jak and Leo sort of worked together and we,

446
00:49:46,270 --> 00:49:55,450
we tried the very first construct and it worked sort of 90% to our satisfaction because we ran into a slight problem

447
00:49:55,450 --> 00:50:00,970
that the original group working with sales had run into that when you're trying to express this thing in yeast,

448
00:50:01,480 --> 00:50:07,510
the yeast has a very simplified well, it's not simple, but it's simple.

449
00:50:07,510 --> 00:50:11,890
It appears simple to us compared to the eukaryotic system for adding sugars to proteins.

450
00:50:12,400 --> 00:50:19,810
And occasionally it seems to go into overdrive and add a huge long chain of mannose is that you don't want.

451
00:50:20,530 --> 00:50:28,690
And we realised that it was doing this and this was upsetting the ability of the RBD to assemble it.

452
00:50:28,770 --> 00:50:32,160
Didn't block it completely, but it was definitely interfering.

453
00:50:32,880 --> 00:50:40,890
So we then worked out which sugar it was by which side, and it was right at the beginning of the, of the second.

454
00:50:40,900 --> 00:50:44,310
So we just chopped it off and that solved the problem. So we haven't had a problem since.

455
00:50:45,240 --> 00:50:52,170
So we make it in yeast now. And the great thing about that is that you can theoretically make huge amounts.

456
00:50:52,710 --> 00:50:58,770
There are very well-defined, you know, GMP processes for making it clean for vaccine.

457
00:50:59,880 --> 00:51:03,570
So we now had production of yeast.

458
00:51:03,570 --> 00:51:08,670
The yeast version worked, so we sent that to an idea and they showed that it worked.

459
00:51:09,240 --> 00:51:15,780
And so we had a production method. Then they did very clever things with the particle.

460
00:51:15,780 --> 00:51:20,189
So the particle was being made in E.coli. E.coli makes lots of endotoxin.

461
00:51:20,190 --> 00:51:32,100
No big companies can deal with that and they make lots of proteins and E coli, but CPI and in general were keen to avoid that if we could.

462
00:51:32,940 --> 00:51:36,990
So they put it into bacillus, which is the milk in a milk bacillus bug,

463
00:51:37,500 --> 00:51:43,860
which makes it beautifully and itself assembles and in the medium around the bug.

464
00:51:44,250 --> 00:51:46,920
And so you don't have to break open the bug.

465
00:51:47,640 --> 00:51:56,760
They worked a way of making it secrete, which they have patented quite rightly, and so now they have a very simple way for making it.

466
00:51:57,090 --> 00:52:05,370
So they make that the particle in the bug particles ready made and we can make the RBD the receptor binding domain in the yeast.

467
00:52:05,610 --> 00:52:08,820
And the two things come together to form a very nice vaccine works.

468
00:52:09,900 --> 00:52:15,000
But we didn't have any funding and we tried again and again from UK right now they weren't going to do it.

469
00:52:15,780 --> 00:52:19,500
And then magic happened and that was Pamela Bjorkman.

470
00:52:19,980 --> 00:52:28,020
So Pamela and I have known each other for 40 years, at least from a very exciting period in 1985, 86,

471
00:52:28,590 --> 00:52:41,400
when Pamela was the student in Normandy's lab crystallising the HLA molecule, the tissue antigens, which we knew were involved in virus recognition.

472
00:52:42,060 --> 00:52:47,219
And I had just found that peptides were the final thing that was being seen,

473
00:52:47,220 --> 00:52:52,200
but we didn't know how the peptide and the damage molecule came together and they just

474
00:52:52,200 --> 00:52:57,209
got the structure and I visited the States 1985 and very much wanted to meet that.

475
00:52:57,210 --> 00:52:59,610
Well, I knew Don Wiley anyway from his visits to England,

476
00:52:59,610 --> 00:53:10,730
but to visit his lab and they showed me the structure as it was pre-publication and there was this oddness that there were too many antimony there,

477
00:53:10,740 --> 00:53:17,610
too many ends. And what they'd found was that they had the structure and then there was this blurry thing in the middle.

478
00:53:18,090 --> 00:53:25,200
And I presented my seminar with all the peptide things, and Don said, It looks like this is probably the peptide.

479
00:53:25,200 --> 00:53:31,230
You know, it's kind of obvious. And that was an incredibly exciting moment and turned out to be right.

480
00:53:31,710 --> 00:53:36,390
And we've remained friends ever since. And I often talked about, you know, worked together before.

481
00:53:36,480 --> 00:53:37,890
Anyway, one day the phone goes,

482
00:53:38,760 --> 00:53:45,659
we didn't know by that stage that Pamela was also doing some work on this system because she she smart and she'd spotted that it

483
00:53:45,660 --> 00:53:54,360
was really powerful and they'd done some work with HIV and it was obvious that make putting our beds on would be a sensible idea.

484
00:53:54,600 --> 00:54:01,739
But she'd come up with a very smart idea, which I think I'm not sure if she was the first they were the first group to think of this.

485
00:54:01,740 --> 00:54:07,410
I think there was another group in America who tried it on flu who'd come up with a concept.

486
00:54:07,680 --> 00:54:14,339
And the concept may be older than that. I ought to know how. Sometimes it's really difficult to find the absolute origin of a good idea.

487
00:54:14,340 --> 00:54:23,220
But, um, and the idea was this, is that if you want to make an anti a vaccine that induces very broad antibodies,

488
00:54:24,180 --> 00:54:35,430
one way conceptually is to have a particle with, say, up to eight different homologous components from different viruses.

489
00:54:36,480 --> 00:54:41,250
And then when the antibody comes along in the lymph node, if it can bind.

490
00:54:42,310 --> 00:54:49,120
Across two of these things that the tape sees that we're talking about, it will have an advantage.

491
00:54:49,120 --> 00:54:52,410
It will be stimulated more effectively because it can hold on for longer.

492
00:54:52,450 --> 00:54:58,029
That's the idea. And so the signal, the B cells will get the signal, whereas if it's only wholly owned by one arm,

493
00:54:58,030 --> 00:55:04,150
it can fall off and it won't get such a strong signal since they've called it avidity advantage, avidity, meaning stickiness.

494
00:55:04,780 --> 00:55:08,800
It's a really neat idea because it's kind of simple in concept and it's simple to test.

495
00:55:09,310 --> 00:55:15,639
And she put the idea was to see if you could get a good vaccine for bat viruses,

496
00:55:15,640 --> 00:55:18,940
because we know there are, you know, tons of bat viruses out there that we're all worried about.

497
00:55:19,490 --> 00:55:22,629
And so she put eight different well,

498
00:55:22,630 --> 00:55:34,330
seven different bat virus rbds and one coded RBD on there and showed that the antibodies that that particle induced were very broad.

499
00:55:35,050 --> 00:55:38,620
And by this stage we were learning where different antibodies bind.

500
00:55:39,040 --> 00:55:46,810
And there are some regions of the RBD that are more conserved even within the variants, so-called class three and four down the bottom.

501
00:55:46,960 --> 00:55:57,670
Well, basically, if you think of a sitting squirrel, the haunches squirrel and sort of feet down, there are more generally more conserved.

502
00:55:57,680 --> 00:56:02,380
And these antibodies tended to go for those areas. So it was a really, really nice concept.

503
00:56:02,770 --> 00:56:07,870
And so she phoned me up and said, Look, I realise I hear that you've got all these other components in place, you know,

504
00:56:07,870 --> 00:56:13,089
the yeast production by the stage we were talking to Andy Pollard who said, yes, they would do the clinical trial for us.

505
00:56:13,090 --> 00:56:14,110
So we had a clinical trial.

506
00:56:14,440 --> 00:56:25,219
We had really good help from William James in in the Dunn's school, who can do the neutralisation assays on the wild type viruses.

507
00:56:25,220 --> 00:56:30,820
So he's a real craftsman at doing that. So we had everything there said, why don't we join forces?

508
00:56:31,390 --> 00:56:38,470
Well, Pamela is, you know, a fantastically you know, she's a real powerhouse.

509
00:56:38,780 --> 00:56:50,590
And we basically took the grants that I'd been writing for the UKRI and added this concept and sent it to Cepi,

510
00:56:50,890 --> 00:56:56,830
who at that time was saying they want ideas for very broadly Cepi and the.

511
00:56:57,040 --> 00:57:02,079
Oh God, I always forget these the and you'll have to look it up.

512
00:57:02,080 --> 00:57:09,069
It's the Coalition for Epidemic Preparedness Innovations.

513
00:57:09,070 --> 00:57:12,580
I think it is. But you need to check that I hate these.

514
00:57:12,690 --> 00:57:16,540
I mean, anyway, CEPI liked it.

515
00:57:16,990 --> 00:57:22,090
They rejected us. You know, that was one of our other objections before we had this addition.

516
00:57:22,090 --> 00:57:24,580
But when we put it all together, they accepted it.

517
00:57:25,240 --> 00:57:37,629
And so it's a joint grant to Caltech and Centre for Process Innovation in general and US, and also includes the clinical trial in Oxford in general.

518
00:57:37,630 --> 00:57:43,330
So clinical trial, done, school contribution, 30 million, $30.4 million.

519
00:57:43,370 --> 00:57:47,230
Right. And you know, sounds a huge amount of money,

520
00:57:47,560 --> 00:57:57,040
but that most of that is actually going to the Centre for Process Innovation to work up the scale up to GMP and the regulation.

521
00:57:57,490 --> 00:58:02,560
You know, just the regulation is everything is so expensive when you get to that's ten times more expensive.

522
00:58:02,980 --> 00:58:08,860
So just doing things like the various things that the regulators need for showing non toxicity in animal models,

523
00:58:09,070 --> 00:58:13,809
it's amazing the expensive to do that to that level of acceptance.

524
00:58:13,810 --> 00:58:21,280
So but for us it means that Jack's funded for four years and then yeah,

525
00:58:22,180 --> 00:58:28,629
we're going to get a we're just about to start interviewing for an experienced technician health

526
00:58:28,630 --> 00:58:35,709
for him research assistant who can help him because each time we change anything on the particle,

527
00:58:35,710 --> 00:58:41,500
we have to put it through the animal model and check that it's still doing what it says on the can, that we're not missing something.

528
00:58:42,130 --> 00:58:48,510
And we probably do that both in Caltech and here so that we always have confirmation in two labs.

529
00:58:48,510 --> 00:58:49,780
So it's a very good thing to do.

530
00:58:50,410 --> 00:58:58,660
And and then to help pay for the very it is expensive to do all the neutralisation assays on the antibodies with real viruses.

531
00:58:58,660 --> 00:58:59,500
We feel that is important.

532
00:58:59,500 --> 00:59:08,200
We, Pamela, does these so-called pseudotyped viruses which give you quite a lot of answers but they're and for some viruses, that's all you can do.

533
00:59:08,590 --> 00:59:15,700
But in general, they're more sensitive and they can give you a little bit more of a rose tinted spectacle

534
00:59:15,700 --> 00:59:22,389
view of what you've got compared to live viruses and obviously an animal model.

535
00:59:22,390 --> 00:59:30,100
We're actually protecting a living organism. And so, uh, so that all came together and Cepi said yes.

536
00:59:30,100 --> 00:59:37,210
So then there was a tremendously long, protracted business going through everything with Cepi.

537
00:59:37,810 --> 00:59:41,350
And because they they don't say they say yes initially.

538
00:59:42,480 --> 00:59:47,340
Providing you meet all our requirements. And quite rightly they're very strict.

539
00:59:47,520 --> 00:59:55,650
So they have a huge panel of people, consultants who come in and ask to bombard you with questions, quite rightly so.

540
00:59:56,370 --> 01:00:05,040
And we were pretty good because a lot of the basic science showing that this thing looks like it should work is there or done or published.

541
01:00:05,730 --> 01:00:16,680
So it's really mainly the CPI work and then we have to test whatever CPI makes and that's going to go both to thing and a little bit of design.

542
01:00:17,010 --> 01:00:22,260
You know, we originally the design had the original Wuhan sequence in it.

543
01:00:22,620 --> 01:00:27,179
We think that might not be such a sensible idea because everybody who's already primed the Wuhan

544
01:00:27,180 --> 01:00:31,530
sequence may just focus on that and not make the antibodies against all the other things.

545
01:00:32,010 --> 01:00:38,669
So we've changed that for the beta variant, which is quite different and that seems to work fine and we have a very nice antibody against that.

546
01:00:38,670 --> 01:00:42,090
So. And that is just starting.

547
01:00:42,090 --> 01:00:52,080
So the funding has just begun and say, we're just interviewing for someone to help Jack to do this cyclic testing of things that come through.

548
01:00:52,440 --> 01:01:00,600
And then we have a bit of money on the side. And I've been we have I have money, you know, a bit of money for here and there to do other ideas.

549
01:01:01,200 --> 01:01:09,560
So one of the things I'm keen on is, of course, keeping the flu work going and we hope to get a bit more funding for that.

550
01:01:09,570 --> 01:01:17,700
Actually, the Chinese Oxford Institute has has refunded, Pamela, to keep that going for a couple of years, which is nice.

551
01:01:18,690 --> 01:01:24,900
And but I am slightly nervous about the variants, the new variants that are coming through,

552
01:01:25,440 --> 01:01:31,500
because they are mutating at a rate we've never seen in flu and they're mutating everything.

553
01:01:32,090 --> 01:01:36,360
So when you look at where the mutations are on your squirrel,

554
01:01:37,050 --> 01:01:42,750
they tended to be over the head of the squirrel and on the sort of saddle area of the squirrel,

555
01:01:42,960 --> 01:01:48,300
because that's where the Ace2 thing binds and that's where the antibodies bind to block the ace2.

556
01:01:48,330 --> 01:01:54,420
So they were clever mutations that actually enhanced ace2 binding while blocking the antibodies binding.

557
01:01:55,390 --> 01:01:58,890
Um, but gradually, you know,

558
01:01:58,890 --> 01:02:06,840
antibodies have been developed with time after multiple vaccinations against the more conserved regions and now they're mutating that.

559
01:02:07,980 --> 01:02:16,650
So that's a real worry for us because to me anyway, Pamela thinks I'm worrying too much, but I tend to worry a lot.

560
01:02:16,650 --> 01:02:24,719
So because our whole concept with this eight mosaic is to make antibodies against these conserved regions,

561
01:02:24,720 --> 01:02:26,640
which works really well for all the bat viruses.

562
01:02:26,910 --> 01:02:33,780
But if these regions mutate enough in new variants, it ain't going to work for the new variants, or it might be weakened.

563
01:02:33,990 --> 01:02:41,160
How can these something as fundamental as the receptor binding domain mutate and still work as a receptor binding domain?

564
01:02:41,310 --> 01:02:49,260
Well, that's the million dollar question. And I'm not enough of a structural biologist to give you an educated answer.

565
01:02:49,680 --> 01:02:57,120
But basically what when, as I understand in my very simple understanding,

566
01:02:57,120 --> 01:03:04,170
is that protein interact and you think it's just one face interacting and fitting against another face.

567
01:03:04,320 --> 01:03:11,220
It's much more subtle than that, that within that interaction there are hotspots that generate binding energy,

568
01:03:11,550 --> 01:03:15,000
and then there are cold spots where you can vary it quite a lot and it doesn't bother it.

569
01:03:15,360 --> 01:03:19,079
And so it's like that. So there are key interactions which can vary a bit.

570
01:03:19,080 --> 01:03:21,420
So if let's say you had three really strong ones,

571
01:03:22,380 --> 01:03:27,780
you might be able to alter it in such a way that the three different really strong ones, but you still get the same binding energy.

572
01:03:28,440 --> 01:03:31,260
That's the concept. There are antibodies like that too.

573
01:03:31,530 --> 01:03:38,210
So now one of the things that's happening, as we analyse more and more antibodies, there are antibodies that are binding.

574
01:03:38,280 --> 01:03:42,600
Originally, the antibodies that bound on the head and these regions were blocked.

575
01:03:42,990 --> 01:03:49,920
All variants that just lost recognition, most of them lost recognition and tonnes of papers claiming the next antibody that was

576
01:03:49,920 --> 01:03:53,220
really cross-reactive and the next variant would come along and block that antibody.

577
01:03:53,730 --> 01:03:59,730
But there are some that are amazingly cross-reactive that still bind in these regions and they're doing the same thing.

578
01:04:00,060 --> 01:04:08,730
They're able to tolerate changes, but they have like a grappling on, as it were, that can bind to a to a dispersed epitope.

579
01:04:08,730 --> 01:04:14,250
So we think of epitopes as being an area of surface to which the antibody binds as it's more subtle.

580
01:04:14,250 --> 01:04:20,129
So you can have a sort of dispersed set of conserved residues which will allow the binding and and of course,

581
01:04:20,130 --> 01:04:25,230
we should be able to stimulate those antibodies, too, with this mosaic concept, which we're hoping we will.

582
01:04:25,620 --> 01:04:33,120
But on the side, one of the things I do want to do now is there are so many variants you could make a mosaic of variants and see how well that worked.

583
01:04:33,120 --> 01:04:37,560
And it's easy for us to do because we've got everything in the freezer. So I do want to do that as we.

584
01:04:37,740 --> 01:04:43,170
So we have a back up plan in case we run into the problem that the antibodies we

585
01:04:43,170 --> 01:04:48,660
generate in people when we we do immunise them turned out not to be so good.

586
01:04:49,090 --> 01:04:52,469
The latest variant which may have mutated all those regions.

587
01:04:52,470 --> 01:05:00,209
So it may turn itself into a virus which is so different to all the bat ancestors, you know, that we run into that problem.

588
01:05:00,210 --> 01:05:05,490
But, but the concept that Pam's come up with, Pamela's come up with.

589
01:05:06,590 --> 01:05:10,490
Is very powerful and in principle you can apply it to other things.

590
01:05:11,300 --> 01:05:15,560
It really works best for small monomeric units like the RBD.

591
01:05:15,950 --> 01:05:22,190
So we're very lucky that this virus is tailor made for this for this technology.

592
01:05:22,460 --> 01:05:25,670
Flu or HIV is much more difficult.

593
01:05:26,900 --> 01:05:33,880
So that was a stroke of luck. And again, it was something that drove us and we tried to get that message across to the funding agencies.

594
01:05:33,890 --> 01:05:36,590
Look, this is the perfect technology for this.

595
01:05:36,590 --> 01:05:46,070
Don't need a cold chain can update very quickly can make it in yeast even if we didn't have the the mosaic concept and still they didn't buy it.

596
01:05:46,610 --> 01:05:53,870
I don't know. But I've never understood funding agencies that there are periods in your life when you just you showered with money.

597
01:05:54,110 --> 01:05:57,830
So at some point I just had so much money, I didn't know what to do with it.

598
01:05:58,790 --> 01:06:05,630
And then there are other times when the work you're doing seems to you to be just as thoughtful and valuable,

599
01:06:05,900 --> 01:06:09,830
and yet you just can't get anybody interested. It's our business.

600
01:06:10,130 --> 01:06:14,959
And then I think funding agencies I mean, I might say things that people don't like now,

601
01:06:14,960 --> 01:06:26,030
but I've noticed over the years the funding agencies become dominated by administration rather than science, and the MRC certainly is like that.

602
01:06:26,510 --> 01:06:36,350
And these are very good administrators, they administer very well, but they shouldn't be developing in their science initiatives.

603
01:06:36,350 --> 01:06:40,669
It should be the scientists doing that. And I do worry about that.

604
01:06:40,670 --> 01:06:47,090
I think in the UK I just huge administration and everything's in one place that's bad.

605
01:06:47,100 --> 01:06:52,940
You need diversity of funding. So I, you know, but I'm retiring soon.

606
01:06:52,940 --> 01:06:56,870
So but I think for the future and this obsession,

607
01:06:56,870 --> 01:07:03,829
that problem and the obsession with spinoffs and secrecy and patents, that means people don't talk as much.

608
01:07:03,830 --> 01:07:09,770
And that means you will not get the Nobel Prize winning work. You can use up all the previous Nobel Prize winning work you've got.

609
01:07:10,250 --> 01:07:16,340
It's like spending the family silver, but coming up with the new things you won't.

610
01:07:16,820 --> 01:07:23,840
That will happen at a lower frequency if your institution is obsessed with this sort of thing and with what I would say,

611
01:07:23,840 --> 01:07:31,490
fashion driven funding agencies, which tend to go for the big groups, fashionable stuff, they're all sitting on, all the committees and all that.

612
01:07:32,060 --> 01:07:35,180
And you need you need some, you know,

613
01:07:35,180 --> 01:07:41,270
benign dictatorships to pick out clever young people and give them funding and have faith

614
01:07:41,270 --> 01:07:48,320
in people and not allow this sort of political stuff to to have too much of a role.

615
01:07:48,980 --> 01:08:00,710
So I personally would revamp the MRC, gives them plenty of power and have it much smaller scale run by scientists with true civil servants,

616
01:08:00,800 --> 01:08:05,330
helping them to run it rather than taking over the running, which seems to me to be what's happening.

617
01:08:05,810 --> 01:08:06,950
I'll get into terrible trouble.

618
01:08:10,280 --> 01:08:18,620
You mentioned Tesco so the this the vaccine isn't the only thing you've been doing in relation to go with you mentioned testing was another yes.

619
01:08:18,620 --> 01:08:28,310
So so worked on. Yes yes. So in I think April of that first year I got a call or an email actually from a very interesting chat.

620
01:08:29,310 --> 01:08:32,680
And, uh, could attend. Um.

621
01:08:34,530 --> 01:08:38,669
What is it about settings that's going on? On my sister, wasn't it? Etienne.

622
01:08:38,670 --> 01:08:43,830
Anyway, he called me and said, Is anyone making an antibody test?

623
01:08:44,970 --> 01:08:47,250
Cheap, easy. And.

624
01:08:47,400 --> 01:08:54,870
And he said, you know, the obvious would be haemagglutinin, which is the old fashioned way of detecting antibodies that are glutamate red cells.

625
01:08:55,860 --> 01:09:04,680
You know, Coombs and Kim's test and the application to infectious disease, which up until about 1966 was the way to do it.

626
01:09:05,370 --> 01:09:10,670
And, uh, and so I listened to that and I thought, well, why not?

627
01:09:10,680 --> 01:09:16,770
You know, we could have a go at this because the RBD is so malleable we can use it and probably attach it to red cells.

628
01:09:17,400 --> 01:09:18,479
So we thought about it.

629
01:09:18,480 --> 01:09:29,559
We did some brainstorming together and found a paper from a Paris group some time ago had shown that they made a single chain antibody.

630
01:09:29,560 --> 01:09:35,250
So from a dromedary and from a molecular biology point of view, they're easier to manipulate.

631
01:09:35,850 --> 01:09:39,690
And that binds to like a foreign on red cells to a conserved bit of like a

632
01:09:39,690 --> 01:09:44,430
foreign like for foreign polymorphic and varies between individuals quite a lot,

633
01:09:44,790 --> 01:09:49,140
or at least in geographical areas and so on.

634
01:09:49,890 --> 01:09:53,310
Anyway, this thing bound strongly to do like a foreign.

635
01:09:53,910 --> 01:10:03,660
And so looking at the structure, it looked easy to just link the receptor binding domain to that, like a foreign binding unit.

636
01:10:03,810 --> 01:10:09,390
And then that should bind to red cells. It shouldn't crosslink the red cells, so they should stay in solution.

637
01:10:09,540 --> 01:10:13,739
And then if you had an antibody that would bind across the red cells and cause it intonation,

638
01:10:13,740 --> 01:10:19,770
which you can see by I, you don't need a very expensive machine and you can titrate it and so on.

639
01:10:20,160 --> 01:10:27,210
So again, we just made it and it worked. First time bingo, just straight off, the very first design worked.

640
01:10:27,850 --> 01:10:31,180
And so we published.

641
01:10:31,550 --> 01:10:36,430
We had to do a lot of control experiments to show that it was real and in know artefact,

642
01:10:36,900 --> 01:10:40,620
you know, but we had all these nice monoclonal antibodies we can do it with and so on.

643
01:10:41,520 --> 01:10:46,830
So I wrote that up because I actually did most of that myself.

644
01:10:47,070 --> 01:10:56,610
I set the assay up and then Pamela and Liza, who's not here today, and we did a lot together and published it.

645
01:10:57,030 --> 01:11:03,390
And I spoke about it to the W.H.O. and said, Look, we're prepared to give this away free because it cost us.

646
01:11:04,110 --> 01:11:11,790
We worked out that it was something like 0.0 $0.07 or less than a penny per test, basically at the simplest level.

647
01:11:12,630 --> 01:11:18,660
Whereas, you know, for any other type of antibody test, you're talking two or £3 a pop for every single one.

648
01:11:19,440 --> 01:11:23,370
And and so we published it.

649
01:11:23,370 --> 01:11:31,049
And I worked out that because I run a little charity that's based on my Jonty prize, which I put into a charitable trust.

650
01:11:31,050 --> 01:11:34,410
So we use that money generated by the trust.

651
01:11:34,590 --> 01:11:37,790
It's just it's for medical research, but we can do any medical research.

652
01:11:37,800 --> 01:11:43,410
So it worked out. We could easily fund people and give them 20,000 tests straight off.

653
01:11:43,410 --> 01:11:47,819
And if they did something interesting with it, we could go on providing it. So we've done that.

654
01:11:47,820 --> 01:11:58,040
And that's proved quite interesting because there's a wonderful person, Nilka, who got a voucher,

655
01:11:58,050 --> 01:12:09,140
who trained here with in the department and now is a senior person in Colombo, and she's done a lot of work with it in the field.

656
01:12:09,150 --> 01:12:11,820
So it really does work in a real place.

657
01:12:12,330 --> 01:12:19,790
And actually I mustn't forget it because he suggested this and he got me going on it and we worked on it together.

658
01:12:19,800 --> 01:12:29,820
You're a senior author on the paper, and then we talk a lot to a group in Bergen.

659
01:12:31,890 --> 01:12:33,480
Dr. Cox, Professor Cox.

660
01:12:33,900 --> 01:12:43,260
And they were interested because they do a lot of fieldwork in Tanzania and they wanted a simple test because again, you can freeze dry this reagent.

661
01:12:43,980 --> 01:12:47,010
And so we sent them lots of stuff.

662
01:12:47,520 --> 01:12:53,909
And by that stage, we were comparing the levels of antibody you could detect with neutralisation assays.

663
01:12:53,910 --> 01:12:58,260
And actually it correlates really very well with neutralisation, with the big study, with the haematologists here.

664
01:12:58,840 --> 01:13:06,930
And and they wanted they did a basically we confirmed each other's work in different cohorts and they did a big cohort.

665
01:13:07,410 --> 01:13:10,649
And William did the assays for us.

666
01:13:10,650 --> 01:13:18,750
They had neutralisation assays. And we, we then looked at different variants and it looked, you know, it's a very good, simple antibody.

667
01:13:19,190 --> 01:13:22,630
You just take a fingerprint, you can do it with. You can do it from a finger prick.

668
01:13:24,060 --> 01:13:29,420
At its simplest, you take a finger prick or a blood sample, take a serum or plasma.

669
01:13:29,440 --> 01:13:40,110
Doesn't matter. And and the indicator cells can be O-negative cells from the blood banks.

670
01:13:40,230 --> 01:13:43,380
Those don't react with anything in the serum.

671
01:13:44,010 --> 01:13:47,970
But some parts of the world, O-negative is a very rare blood group,

672
01:13:48,300 --> 01:13:51,360
and those are the kinds of parts of the world where this test might be quite useful.

673
01:13:52,020 --> 01:13:55,980
So you can do it with the person's own red cells.

674
01:13:56,130 --> 01:14:01,380
And the two ways of doing that, you can just dilute the blood one in 40 and add the reagent,

675
01:14:01,380 --> 01:14:08,610
and that gives you a a plus minus test at one in 40 and or if more clunky.

676
01:14:08,610 --> 01:14:15,509
But you have to wash the red cells to free them from any antibody and then you can use them just like you would the O-negative cells,

677
01:14:15,510 --> 01:14:19,589
because it's their own blood. So they're not going to make their own red cells, and that works fine.

678
01:14:19,590 --> 01:14:25,860
And that's how we do it in the lab to find out each other's levels. And that's been quite popular.

679
01:14:25,860 --> 01:14:32,370
I mean, we've sent it out. We've sent out about 30 or 40 aliquots around the world.

680
01:14:33,300 --> 01:14:38,850
Of those I mean, what happens when people request these things is that I'm afraid about 90% of the

681
01:14:38,850 --> 01:14:42,990
time it goes in the freezer or into the fridge and never comes out again because,

682
01:14:43,350 --> 01:14:49,380
you know, the relevance begins to wane because now that probably 90% of the world are positive for antibodies.

683
01:14:50,550 --> 01:14:55,590
What's it going to tell you? Of course, it might help you tell who's going to get seriously ill or not,

684
01:14:55,590 --> 01:14:59,340
because if you had an antibody level above a certain level, we haven't been able to define that.

685
01:14:59,340 --> 01:15:03,510
But if we had if we knew that and say, well, if you've got this level against this variant,

686
01:15:03,510 --> 01:15:06,150
you're not going to get sick, that would be quite useful, I think.

687
01:15:06,630 --> 01:15:14,670
And for elderly people, you know, I was I had these pipe dreams of of the visiting, you know, in some parts of the world,

688
01:15:14,670 --> 01:15:17,490
like we were hoping to do some work with Cuba,

689
01:15:17,940 --> 01:15:24,930
but it was impossible because American the American customs wouldn't allow us to import the reagent again.

690
01:15:25,110 --> 01:15:31,560
It was impounded. I mean, but they've done very well because they made their own vaccine.

691
01:15:31,590 --> 01:15:37,440
I have to greatly admire what they've done. And then they were interested.

692
01:15:38,100 --> 01:15:42,719
So. So you get people who are interested and then they can use it because you don't need equipment.

693
01:15:42,720 --> 01:15:46,290
Just hold it up to the light and you see where you've got your agglutination and that's it.

694
01:15:47,140 --> 01:15:58,380
And so Burgin have done a lot and Natick has done a lot in, in and in Lanka.

695
01:15:59,010 --> 01:16:06,870
And we've got a colleague in South America in and, uh, where is he?

696
01:16:07,290 --> 01:16:14,280
He hasn't published anything. They keep sending us bits of data on his hospital staff, basically, and so on.

697
01:16:14,970 --> 01:16:19,980
But it hasn't. I mean, it's not like there are 20 groups using it.

698
01:16:19,980 --> 01:16:23,760
There's maybe five, maybe more, maybe some we haven't heard of.

699
01:16:23,910 --> 01:16:30,780
We had a visit actually from someone working in in Africa who's used it and he's adapted it slightly.

700
01:16:31,140 --> 01:16:36,210
And so there are people and every now and then we do say to them, you want more,

701
01:16:36,480 --> 01:16:41,340
we'll always send you more, because we it for us it's incredibly cheap because we might.

702
01:16:41,490 --> 01:16:47,220
The charitable organisation pays for it and we either make it ourselves and send it to them or we get absolute antibody to make it.

703
01:16:48,280 --> 01:16:58,970
And. So that's been fun. Not game changing, but at least it's something that's for people working in countries where they have literally no money.

704
01:16:59,330 --> 01:17:02,690
They can do research with this and get some information.

705
01:17:02,930 --> 01:17:07,360
And in the early days, it was quite useful for telling what proportion of people had been infected.

706
01:17:07,370 --> 01:17:11,380
So in Colombo, of course, in the poorer areas it was very high.

707
01:17:11,390 --> 01:17:18,590
50, 60% of people were seropositive, whereas in the more affluent areas it was lower, so and so on.

708
01:17:18,950 --> 01:17:22,490
Yeah. And I also had a note about therapeutic antibodies.

709
01:17:22,730 --> 01:17:29,870
Yes. Yes. There being antibodies. Yes. Well, and we were making lots of monoclonal antibodies to flu.

710
01:17:30,320 --> 01:17:33,469
And then after we thought about making them ourselves here,

711
01:17:33,470 --> 01:17:38,510
but we were doing so many other things because we got all the technology and everything and we thought about how to do it,

712
01:17:38,510 --> 01:17:43,249
but it is very labour intensive. One other hung in Taiwan.

713
01:17:43,250 --> 01:17:49,700
This was a student here, but Arthur got going on it absolutely immediately and was actually really one of the first

714
01:17:49,700 --> 01:17:54,290
people in the world to isolate monoclonal antibodies and was sending them to we had a sort of

715
01:17:54,590 --> 01:17:58,190
arrangement that he'd send them to us and we characterised them on the different variants and

716
01:17:58,190 --> 01:18:06,950
over weren't variants of that stage but on virus and neutralisation and that and but we were,

717
01:18:07,070 --> 01:18:16,460
we were not it wasn't the foot was not full on the accelerator because we wanted to, you know, take our time over it.

718
01:18:17,420 --> 01:18:22,760
So his paper was published rather late and lots of other people, of course, were doing it.

719
01:18:22,760 --> 01:18:25,520
And Gavin Scruton has done a fantastic job.

720
01:18:25,520 --> 01:18:32,900
He really focussed on it and he has a group of really, really skilled crafts and around him craftspeople I should say.

721
01:18:33,410 --> 01:18:36,420
And they've done a fantastic job as a series of papers.

722
01:18:36,420 --> 01:18:41,840
And so looking at monoclonal that define the different variants and the escape and everything else,

723
01:18:42,110 --> 01:18:47,300
working with structures with Dave Stewart who helped us originally to this, we did some structures with them.

724
01:18:47,840 --> 01:18:58,760
So that's been very, very attractive as a way of either therapy or protection because as you know,

725
01:18:58,760 --> 01:19:05,210
there's been quite a lot of publicity recently, about half a million people in the country who don't respond to the vaccine.

726
01:19:05,630 --> 01:19:15,080
And we know from other examples like protecting children against and promptly,

727
01:19:15,080 --> 01:19:20,000
but you can protect people with monoclonal antibodies and there are ways of making them long lived.

728
01:19:20,000 --> 01:19:23,780
People done very clever stuff in terms of making them long lived.

729
01:19:23,780 --> 01:19:27,470
So you may only need to inject it every few months and they get protection.

730
01:19:28,280 --> 01:19:33,530
And it's actually extraordinary that this has not happened yet here.

731
01:19:33,860 --> 01:19:42,330
Now, A-Z have produced their combination of antibodies, which up until now looked really strong.

732
01:19:42,350 --> 01:19:51,330
The problem is of the two antibodies in that mix, one now is completely lost its activity on Omicron and the other one is reduced.

733
01:19:51,350 --> 01:19:56,930
So overall, most people find that that combination has got at least an eight fold reduction.

734
01:19:57,050 --> 01:20:04,940
Would that be protective or not? There is some field study work in other places where there are claims that it is still protective.

735
01:20:05,270 --> 01:20:09,379
But I can see I can see the rationale for wanting nice to look at it because you're

736
01:20:09,380 --> 01:20:14,240
talking about a huge outlay of money and if it doesn't work or worse still,

737
01:20:14,240 --> 01:20:17,780
it gives people confidence to go out into the world and then they get infected.

738
01:20:17,930 --> 01:20:22,370
That would be a real disaster. So there are reasons for being uncomfortable.

739
01:20:22,790 --> 01:20:29,219
But what does strike me is that between us, for instance, Gavin, many other people,

740
01:20:29,220 --> 01:20:33,950
I mean, there are thousands of antibodies that would be protective against Macron.

741
01:20:34,130 --> 01:20:37,430
Why on earth are we has it been so slow?

742
01:20:37,670 --> 01:20:40,910
And the reason is, of course, regulatory issues are huge.

743
01:20:41,270 --> 01:20:44,690
Things need to go slowly. It needs to go through a monster range.

744
01:20:44,990 --> 01:20:53,090
But we need to revise this because if you're ever going to use antibodies during a pandemic, we need a quick way of doing it now.

745
01:20:53,090 --> 01:21:00,830
Many years ago now, ten years ago, I got a meeting together with the MRC to discuss this very issue and a few,

746
01:21:00,920 --> 01:21:02,470
you know, we got some really good talks,

747
01:21:02,480 --> 01:21:09,440
nobody showed the slightest interest and we had a big meeting with one of the big antibody producing companies

748
01:21:09,590 --> 01:21:16,070
and actually went to the regulators at the time to discuss making them quickly what would regulation require.

749
01:21:16,220 --> 01:21:23,720
And it wasn't impossible. I mean, it could be done and you could actually have everything done probably in a few months or even less.

750
01:21:24,350 --> 01:21:26,479
But it somehow isn't happening.

751
01:21:26,480 --> 01:21:34,580
And for it to all taken this long, I mean, Arthur has a pair of antibodies that would definitely protect against these.

752
01:21:34,910 --> 01:21:39,710
Everything in vitro would suggest that, and I'm sure Gavin does to lots of lovely antibodies.

753
01:21:40,250 --> 01:21:44,719
Why on earth isn't there a system for doing it quickly?

754
01:21:44,720 --> 01:21:48,920
And my pipedream again would be that the, you know, the NHS makes.

755
01:21:48,990 --> 01:21:53,670
Its own blood products. They have five factories that do this very, very effectively.

756
01:21:53,880 --> 01:21:58,310
And they they distribute them around the world. They could make these monoclonal antibodies.

757
01:21:58,330 --> 01:22:05,729
You could have a you can have a whole production system nationalised in the NHS and you could switch quickly could you.

758
01:22:05,730 --> 01:22:16,200
If you. Well I believe you could. Yeah, I believe you could but you'd have to have a regulatory system for accepting a change and accepting that

759
01:22:16,200 --> 01:22:21,810
when you change something there's obviously a very small risk that it's going to have some idiosyncratic,

760
01:22:21,900 --> 01:22:29,880
unpleasant effect on somebody. But the likelihood of that, given the overall experience, I would say, is pretty low.

761
01:22:30,360 --> 01:22:33,450
Now, is there to the some of the best people in the world?

762
01:22:33,450 --> 01:22:38,790
I mean, the Cambridge group have produced tonnes of therapeutic antibodies.

763
01:22:38,790 --> 01:22:42,450
So if anybody can could work out a way of doing it quickly, it would be them.

764
01:22:42,900 --> 01:22:51,450
But it seems to me that it's one thing producing an antibody to treat cancer or treat an autoimmune disease because it's there all the time.

765
01:22:51,450 --> 01:22:56,040
You can spend years getting the regulation right, but when you've got something like this,

766
01:22:56,250 --> 01:23:00,390
it needs to be done quick and we need to work out ways of doing it quick.

767
01:23:00,720 --> 01:23:07,470
And it's not impossible. It's entirely possible because you can make grams of antibody in a week, you know, within modern methods.

768
01:23:08,490 --> 01:23:14,760
But we need a we basically I think you need a whole different regulatory set up for this setting.

769
01:23:15,450 --> 01:23:20,130
And so we now have all these institutes for pandemic preparedness.

770
01:23:20,340 --> 01:23:22,470
Whether they are to tackle this or not, I don't know.

771
01:23:22,740 --> 01:23:29,760
I did briefly sit on the one here and the discussions were so broad covering everything from psychology to,

772
01:23:30,090 --> 01:23:35,069
you know, t cell vaccines, you know, you can't do that.

773
01:23:35,070 --> 01:23:38,220
You've got to be focussed. So personally I think you have to be very focussed.

774
01:23:40,370 --> 01:23:43,850
But half a million people needing protection. That's a lot of people.

775
01:23:43,880 --> 01:23:48,500
Yes. Yes. Huge benefit to them, right.

776
01:23:49,630 --> 01:23:58,150
And. So I'm just going to switch a little bit on the personal impact of the of the the whole sort of pandemic situation.

777
01:23:58,180 --> 01:24:07,700
Yeah. You. Yes. So how how did the that the how the the regulations that came in to to reduce the spread of infection.

778
01:24:07,720 --> 01:24:10,860
Yes. Impact on what you were able to. Yes. You and your colleagues. Right. Yeah.

779
01:24:11,320 --> 01:24:19,030
So those we have an excellent biological safety group here and of course, the university.

780
01:24:19,540 --> 01:24:21,999
And there was basically a dispensation.

781
01:24:22,000 --> 01:24:32,420
If you were if your work was directly relevant to the pandemic, we could go on working, providing we observed very particular rules,

782
01:24:32,650 --> 01:24:45,160
obviously hand washing, all the usual things, the masks and preferably the FP twos and a white coat and everything and separation in the lab.

783
01:24:45,160 --> 01:24:52,960
So I think we were only allowed to people in the lab at once. And and we stuck to that obviously, and we were inspected and everything.

784
01:24:53,680 --> 01:24:59,469
But because I mean, Pramila and Jack are powerhouses.

785
01:24:59,470 --> 01:25:04,030
And so we worked out timing and everything. And then Priscilla was had had her baby.

786
01:25:04,570 --> 01:25:08,890
But it just amazing how much work someone can do.

787
01:25:09,070 --> 01:25:13,810
There's no distractions and no seminars. And then, you know, of course, it's all on Zoom.

788
01:25:14,290 --> 01:25:22,870
And we had regular meetings by Zoom or if I was coming in, I tended to be a sort of troglodyte and come in at night or on weekends,

789
01:25:23,580 --> 01:25:26,830
and we talked regularly about what was going on,

790
01:25:26,830 --> 01:25:32,770
had regular meetings with with our colleagues and with Pamela and everything and all worked that worked very well.

791
01:25:32,770 --> 01:25:37,719
The Zoom meetings worked very well, actually, and Jack got a huge amount done for me.

792
01:25:37,720 --> 01:25:46,840
I got a huge amount done. You know, all these collaborations going somehow it worked and it reminded me of when I first came here and when I

793
01:25:47,320 --> 01:25:55,209
just finished my PhD and Peter Morris very kindly cut off one end of his very big lab and gave it to me.

794
01:25:55,210 --> 01:26:00,610
He said, That's your lab, and I could organise it exactly as I wanted and I no distractions.

795
01:26:01,000 --> 01:26:04,750
So I worked and Francis Scotch and we let Francis Scotch work with me.

796
01:26:04,750 --> 01:26:15,579
He was again fantastic. And we, we had the incubator gels pinch running this or that and I had a chair like this with

797
01:26:15,580 --> 01:26:20,770
wheels on it and I could just move around and we got the huge amount of work done,

798
01:26:21,160 --> 01:26:24,610
just the two of us, and that that's what happens.

799
01:26:24,610 --> 01:26:29,349
If you can really focus and you're not constantly distracted with committee meetings and this

800
01:26:29,350 --> 01:26:33,040
and that and going to this seminar and making sure you've been out to lunch with this person,

801
01:26:33,040 --> 01:26:36,400
it you know, and I think the students had it tough.

802
01:26:36,730 --> 01:26:43,180
So we we have a new student just starting it in the middle of all that.

803
01:26:43,600 --> 01:26:50,379
And I think it's been hard for her, but we've tried very, very hard now to have regular twice weekly meetings.

804
01:26:50,380 --> 01:26:57,100
Actually, we have a lab meeting always. Everybody has a should have show and tell and and then we have individual meetings

805
01:26:57,100 --> 01:27:04,929
and and I like with the Dphil students to in the last sort of period and it can

806
01:27:04,930 --> 01:27:09,280
be longer or shorter depending on how they're doing and everything else to have a

807
01:27:09,280 --> 01:27:14,049
weekly thesis orientated meeting to begin to plan out how the chapters will look,

808
01:27:14,050 --> 01:27:21,490
what the overall point will be, and so on. And that way it's much easier when it comes to actually writing it up that it's have rules in place.

809
01:27:21,490 --> 01:27:23,290
I'm sure it's but I mean it's like writing a book.

810
01:27:23,290 --> 01:27:29,680
It is a book and it can be a very pleasurable thing to do actually if, if there's lots of nice data and so on.

811
01:27:30,550 --> 01:27:36,940
And so we're trying to do that and yeah, mean that all sounds quite positive.

812
01:27:36,940 --> 01:27:45,610
Do you think any of those the lessons learned from that can be continue to be applied now things are, as it were, back to normal.

813
01:27:49,260 --> 01:27:55,100
I don't know. I mean, human nature doesn't tend to learn from experience very much, do we?

814
01:27:55,100 --> 01:27:58,640
I mean, we we do. But by the time you've learned it, you're retiring.

815
01:27:59,210 --> 01:28:02,330
And and this university,

816
01:28:02,330 --> 01:28:11,000
we're quite good at respecting the retired group of people who do come back and remind us about lessons that happened in their lifetimes.

817
01:28:11,690 --> 01:28:17,660
But even then, we don't tend to listen. We tend to always make tend to go around in the same make the same mistakes.

818
01:28:18,350 --> 01:28:24,080
And I think it's inevitable. I think gifted people learn from their mistakes.

819
01:28:24,230 --> 01:28:28,040
It's the it's one of the key features of the most gifted people.

820
01:28:28,550 --> 01:28:32,300
And and they're not afraid about making mistakes.

821
01:28:32,300 --> 01:28:36,230
And I was talking we have a visitor here from Spain for the summer,

822
01:28:36,740 --> 01:28:43,070
and he's done a project which I was quite keen on and I'm still keen on, but the poor chap has been clean negative.

823
01:28:43,340 --> 01:28:47,930
We had an initial positive looking result and he's gone through, done everything perfectly.

824
01:28:47,930 --> 01:28:52,790
I mean negative, you know, it's very disappointing, but that's life.

825
01:28:53,880 --> 01:29:01,560
My experience is that 90% of the ideas I've had for projects don't work or go wrong or, you know, there's some problem.

826
01:29:01,980 --> 01:29:04,680
And that's the way it is. And that's what, again,

827
01:29:05,070 --> 01:29:14,780
if you have a granting agency that's only run by essentially is run by the administrators who only understand positive results, they don't get that.

828
01:29:14,790 --> 01:29:18,540
You know, you've got to fund things that have a high chance of not working.

829
01:29:18,960 --> 01:29:25,260
And one of the reasons I think they stopped funding project grants for young people was that they said the yield was so low.

830
01:29:25,500 --> 01:29:28,649
That's a good thing. That's science. That's what it should be.

831
01:29:28,650 --> 01:29:35,219
Yes. And giving all the money to very big groups run by people who don't do practical things anymore.

832
01:29:35,220 --> 01:29:39,300
I mean, I worry about senior scientists sitting in offices and aeroplanes.

833
01:29:39,690 --> 01:29:47,009
They completely lose touch with the reality of how difficult it is and how how gels go wrong all the time.

834
01:29:47,010 --> 01:29:51,959
How these experiments are not easy takes craftsmanship and they lose.

835
01:29:51,960 --> 01:29:55,830
I think they don't twig that that the craftsmanship is the key thing.

836
01:29:56,400 --> 01:30:01,440
And and certainly people who've only done a very little bit of science and then become a scientific administrator,

837
01:30:01,740 --> 01:30:12,330
I don't I think most of those people don't have that in their bones, you know, and and that so failure is part of success.

838
01:30:12,330 --> 01:30:20,100
You don't have to be incredibly lucky to do a project that's a huge success and get your niche papers and everything just off like that.

839
01:30:20,100 --> 01:30:27,630
I mean, it does happen and it goes to people's heads and it can be a very bad thing because because the likelihood is that the next five years,

840
01:30:28,140 --> 01:30:32,640
again, to be Barry, you know, will be tough if they're trying to do interesting things.

841
01:30:32,640 --> 01:30:37,940
So it's just the nature of it. Um.

842
01:30:38,750 --> 01:30:42,049
So did you. Did you? I mean, I know you've been very unwell in the past.

843
01:30:42,050 --> 01:30:45,470
Did you feel personally feel threatened by catching the virus?

844
01:30:46,850 --> 01:30:55,310
Well, I you know, I looked at the statistics, so at the beginning, we were told that if you are hypertensive and overweight and over 65,

845
01:30:55,640 --> 01:31:03,080
you had a 10% chance of ending up in ITU and maybe, maybe a few percent of dying.

846
01:31:03,650 --> 01:31:08,180
And I fitted that demographic completely at the time.

847
01:31:08,930 --> 01:31:15,770
So I thought, well, the first thing I got to do is listen weights. So I did that and I just behaved sensibly.

848
01:31:15,770 --> 01:31:20,690
We, we avoided contact and I did all my Zoom meetings.

849
01:31:20,690 --> 01:31:24,320
I came into the lab, but I made sure that we were really careful.

850
01:31:24,500 --> 01:31:33,110
Nobody got COVID at that stage. And so from that point of view, I wasn't too worried.

851
01:31:33,110 --> 01:31:39,739
I mean, I thought, you know, being in a place, you know, where I have huge faith in my colleagues,

852
01:31:39,740 --> 01:31:44,120
I thought, well, I probably wouldn't let me die and I'd probably be all right and I'm quite fit.

853
01:31:44,120 --> 01:31:50,839
Otherwise, I got over the cancer. I don't have immune deficiency and I just thought I was overweight, so I needed this weight.

854
01:31:50,840 --> 01:31:57,170
So I did that. But, uh, so I wasn't, I wasn't frightened in that sense.

855
01:31:57,470 --> 01:32:01,460
I just thought, you've got to be sensible, um, which we did.

856
01:32:01,580 --> 01:32:04,520
And then the vaccine, you know, I did get,

857
01:32:04,940 --> 01:32:14,900
I had periods when I sort of wrote to lots of people because I did feel I did feel that some of the things that were being done were bonkers,

858
01:32:15,050 --> 01:32:21,470
you know? I mean, I didn't like the idea of deliberately infecting young people with the virus experimentally.

859
01:32:21,710 --> 01:32:27,770
I think now it's maybe slightly different that we've got various treatments and so forth, but at the beginning you mean challenge studies?

860
01:32:27,770 --> 01:32:30,080
Yes, challenge studies. I was very against it.

861
01:32:30,320 --> 01:32:36,979
And there are all these philosophers of science saying they thought it was all right, but they were all over 65.

862
01:32:36,980 --> 01:32:42,770
Would they be happy for their children to be in this with a 15% of roughly 15% long COVID?

863
01:32:42,770 --> 01:32:44,030
And we didn't know what that was.

864
01:32:44,930 --> 01:32:52,940
And and I felt that we weren't going to learn anything really from it because the people who get sick or the old people and

865
01:32:52,940 --> 01:32:58,190
you're not going to deliberately infect them and the young people don't get this horrible inflammatory reaction in their lungs.

866
01:32:58,340 --> 01:33:11,260
So what are you going to learn? I thought it I just thought it was the wrong thing to do.

867
01:33:11,680 --> 01:33:17,470
And when I tried to talk to people, they wouldn't talk to me. I mean, I wrote to the people doing it here and they wouldn't reply.

868
01:33:18,100 --> 01:33:24,010
You know, I was very upset by that. And I lost my respect, actually, for someone who's who's backed it.

869
01:33:24,730 --> 01:33:31,150
And I cannot see well, I've never been convinced. And one of the senior ethical people here, Tony Hope,

870
01:33:33,100 --> 01:33:38,319
initially was in favour of it because he'd been sold the argument that a small

871
01:33:38,320 --> 01:33:43,420
risk to the individual being affected was worth the big benefit for humanity.

872
01:33:43,600 --> 01:33:46,899
That is a very, very dangerous argument, as you can.

873
01:33:46,900 --> 01:33:54,160
You know, I think that's a terrible argument. But I went through it with him without saying what my thoughts were.

874
01:33:54,160 --> 01:33:57,540
I just went through the facts and he changed his mind.

875
01:33:57,550 --> 01:34:01,770
He said, I absolutely agree with you that there is a risk.

876
01:34:01,780 --> 01:34:07,690
It's all about the risk level for the individual you're infecting and not the benefit that might come out of it.

877
01:34:07,990 --> 01:34:15,910
And and the risk level was too high, but they claimed that it was safe and they claim there wasn't anybody who got long-covid and so forth and so on.

878
01:34:15,910 --> 01:34:19,030
But the principle it was the principle. I thought it was wrong.

879
01:34:19,660 --> 01:34:22,510
And I don't think we've learned anything value from it personally.

880
01:34:22,720 --> 01:34:30,340
But so I got worked up about that and I got very worked up about the reduction of restrictions,

881
01:34:30,340 --> 01:34:36,219
I think, in 2020 and then all that eat out and stuff, it just idiotic.

882
01:34:36,220 --> 01:34:42,730
It was like leaving burning coals in a dry forest when there's a wind blowing and saying It's all right now and just walking away.

883
01:34:43,090 --> 01:34:48,580
Because it was absolutely clear if one of a thousand people still had the virus, very soon, it would just and it did.

884
01:34:48,970 --> 01:34:51,250
And that, you know, a lot of people died.

885
01:34:52,240 --> 01:35:00,520
Now, of course, we see it just the biological angle, not from the whole picture of the economy and all of that.

886
01:35:00,520 --> 01:35:08,920
And but some countries managed to hold on to lockdown until the vaccine was available, and that would have been biologically the sensible thing to do.

887
01:35:09,250 --> 01:35:15,159
But, you know, so I did find myself I think some of my friends thought I was losing it.

888
01:35:15,160 --> 01:35:19,660
Sometimes I think it was I wrote them. But, you know, we've got through it.

889
01:35:19,660 --> 01:35:28,390
But I'll be very interested to see, you know, with this with this review or investigation into how everything was conducted,

890
01:35:28,870 --> 01:35:36,520
what they come up with and how politicised that will be, you know, because obviously there was all the nonsense about contracts and so on.

891
01:35:36,700 --> 01:35:39,250
People basically had this chicken behaviour.

892
01:35:39,880 --> 01:35:50,320
But uh, to me, I mean I think we could have done much better in terms of locking down that because lockdown,

893
01:35:51,280 --> 01:35:58,629
the principle is if you're separate, you're not going to infect people. So but to allow big sporting events to go on when we knew there was terrible

894
01:35:58,630 --> 01:36:04,360
trouble brewing and the whole earlier attitude did seem to me terribly cavalier.

895
01:36:04,450 --> 01:36:15,910
And and and the. Yes, this notion of herd immunity that was going down into the well, the concept of herd immunity is fine.

896
01:36:16,210 --> 01:36:24,520
It is that if you let's say you have mild, mild, a mild illness and everybody gets the mild illness that gives you herd immunity.

897
01:36:24,940 --> 01:36:35,379
The problem is it wasn't a mild illness. And the people advocating this were basing it on wildly optimistic view.

898
01:36:35,380 --> 01:36:40,780
And there was a person, his name I probably shouldn't mention, but who gave it at a talk?

899
01:36:40,930 --> 01:36:49,629
And, you know, we said, well, how can you possibly, you know, justify that when we know that something like 1% of the people,

900
01:36:49,630 --> 01:36:53,890
at least 1% of the people who catch this illness over the age of 60 will die.

901
01:36:54,190 --> 01:36:58,899
You know, and and then the epidemiologist did the calculations and went to the primaries and said,

902
01:36:58,900 --> 01:37:04,390
look, you're talking about 400,000 deaths if you pursue this. And I don't know all the details.

903
01:37:05,170 --> 01:37:07,720
And, of course, I mean, emotions were running high,

904
01:37:08,350 --> 01:37:17,110
but I got the feeling that number ten were almost sifting advisers for those that said what they wanted to hear.

905
01:37:17,410 --> 01:37:21,430
That was my impression, of course, that that would be totally denied, I've no doubt.

906
01:37:22,060 --> 01:37:25,960
And there were some people saying things that they were not qualified to say.

907
01:37:26,290 --> 01:37:33,009
I mean, no doubt about it. And, you know, in my view, you know, it's just my view.

908
01:37:33,010 --> 01:37:41,830
And so but I think I mean, we wouldn't have known that at the time, but in fact it hasn't behaved the way other waves of infection,

909
01:37:42,490 --> 01:37:50,379
epidemic waves, uh, in the, the, the possibility of becoming reinfected seems to be quite yes.

910
01:37:50,380 --> 01:37:57,880
That sort now. Yes, it's been that, that has been a surprise that despite having quite high antibody levels that the new

911
01:37:57,880 --> 01:38:02,620
variants are able to get through the antibody wall and give you a moderate infection.

912
01:38:02,980 --> 01:38:07,720
For some people, it's not so moderate, of course. So I think the last thing.

913
01:38:07,910 --> 01:38:12,050
That's 900 deaths per week of people with COVID now.

914
01:38:12,060 --> 01:38:17,130
How many of those 900 are due to COVID? I know that's the argument, but it's still a some of them are.

915
01:38:17,240 --> 01:38:22,010
And you mentioned you yourself had been quite unwell having been vaccinated how many times?

916
01:38:22,040 --> 01:38:27,919
Oh, I was back in 93 times. Yeah, I lost I lost three kilograms in weight and I've only just recovered that.

917
01:38:27,920 --> 01:38:32,390
That was about two months ago and I was Yeah.

918
01:38:32,960 --> 01:38:37,490
Knocked off even more than usual for four.

919
01:38:37,490 --> 01:38:42,240
But, but, but you know, that's better than obviously ending up in hospital.

920
01:38:42,270 --> 01:38:49,150
Yes. Yes. And but but it's across the country, repeated across the country that level of absenteeism.

921
01:38:49,170 --> 01:38:59,180
Huge. Economic. Huge. Yes, huge. Yeah. No, I think it's always easy to be critical and it's easy to sit in one's, you know,

922
01:38:59,480 --> 01:39:09,110
in one's academic from one's academic position to see that in an ideal world with an infinite resources, how you might do it differently.

923
01:39:09,730 --> 01:39:17,090
Um, and of course we don't have infinite resources and those, you know, economic collapse is not something you, you want.

924
01:39:17,090 --> 01:39:23,540
But, but at the time the argument was really the NHS collapsing because that would, that would have been utterly awful.

925
01:39:24,170 --> 01:39:27,730
And so yeah. Yeah.

926
01:39:28,390 --> 01:39:39,400
I think the whole I think there's a lot to be learned by psychologists, you know, about the way people behave in pandemic situations.

927
01:39:39,400 --> 01:39:47,100
And there are some old stories about this of, you know, cholera epidemics and in big towns and what sort of went on.

928
01:39:47,710 --> 01:39:52,390
And people you would never expect behave in very old ways sometimes in these settings.

929
01:39:52,780 --> 01:39:56,979
And understanding that to some level and being prepared for it, I think,

930
01:39:56,980 --> 01:40:02,650
is part of pandemic preparedness that I think is very important and also very interesting.

931
01:40:03,160 --> 01:40:06,040
What is it that drives certain behaviours?

932
01:40:07,120 --> 01:40:13,480
And I mean this is headless chicken behaviour which is sort of grabbing at straws which you can understand easily,

933
01:40:13,840 --> 01:40:19,540
but more complex things of people pushing themselves forward as experts when they're not experts,

934
01:40:19,720 --> 01:40:22,780
but they're not prepared to admit it, that sort of thing.

935
01:40:23,050 --> 01:40:27,280
And there's a lot of that. I mean, I felt there was a lot of that. Every week the BBC would wheel someone out.

936
01:40:27,550 --> 01:40:31,990
I thought, Well, what authority does that person have saying that?

937
01:40:32,590 --> 01:40:37,360
And the word. And in contrast to that, I think it's probably now felt that people,

938
01:40:37,690 --> 01:40:42,010
as long as they have clear messaging, the population as a whole are much more compliant.

939
01:40:42,040 --> 01:40:52,870
Yeah, nobody expected that whole tearing thing was to me biologically pure nonsense because you either separate or you don't separate half separate.

940
01:40:53,230 --> 01:40:58,330
And then you had this ridiculous business of one mayor of one city complaining about the

941
01:40:58,330 --> 01:41:04,510
tearing in a city some distance away because they had only half as many infections.

942
01:41:04,660 --> 01:41:08,350
Well, that's one one day's worth of viral replication.

943
01:41:08,350 --> 01:41:15,970
You know, it's nonsense. Absolute nonsense. And and the whole theory in the administration of all that must have been very expensive.

944
01:41:16,450 --> 01:41:21,969
And then the testing, you know, test and trace being taken out of the hands of the NHS.

945
01:41:21,970 --> 01:41:29,620
As I understand it, that was mad because they're really experienced and some of the people running the testing have become multimillionaires.

946
01:41:30,070 --> 01:41:38,710
And yet what was the benefit, you know, for us in terms of early diagnosis and so on and all that?

947
01:41:38,750 --> 01:41:42,760
I don't I mean, again, I don't want to talk about it because I'm you know,

948
01:41:42,760 --> 01:41:46,570
I know no more about this than any other ordinary person in the street, really.

949
01:41:47,110 --> 01:41:53,409
But I did feel that there was some strange decision making in that time.

950
01:41:53,410 --> 01:41:59,890
And I think that's part of the psychology of the epidemic pandemic that people do make slightly irrational,

951
01:42:00,670 --> 01:42:03,910
poorly thought out decisions that have huge consequences.

952
01:42:04,780 --> 01:42:08,980
And and how do you prevent that? It's tough.

953
01:42:11,980 --> 01:42:16,720
Maybe you never can. I think we've just about come to the end.

954
01:42:18,760 --> 01:42:21,190
So, yes, this is usual. Final question.

955
01:42:21,190 --> 01:42:31,569
How has the experience of working through the pandemic and the pandemic changed your attitude to your work and or your approach to your work?

956
01:42:31,570 --> 01:42:34,270
And is there anything you'd like to see change in the future?

957
01:42:35,890 --> 01:42:40,900
No, it hasn't changed my attitude to the work because we've been doing what we would be doing,

958
01:42:41,260 --> 01:42:44,450
not in the pandemic, but just rather more of it in the times.

959
01:42:44,490 --> 01:42:54,370
It's been rather more compacted. So we have been very, very busy. But from a scientific point of view, it's been tremendously interesting.

960
01:42:54,920 --> 01:42:59,379
And we've worked with colleagues, brilliant colleagues.

961
01:42:59,380 --> 01:43:09,800
So all these years of scientific friendships and attitudes have come together in this tremendously powerful list.

962
01:43:09,850 --> 01:43:17,020
This we're now called What are we called? I just like referring to us as a collaborative group, but we're all.

963
01:43:17,510 --> 01:43:24,100
They have lovely names for all these things. But I, I, I've enjoyed that enormously.

964
01:43:24,100 --> 01:43:35,740
I've enjoyed seeing Jac and Pramila and Liza, you know, evolve into this and to see all that training and experience.

965
01:43:36,700 --> 01:43:44,469
Being, you know, used in a really productive way and they are very open.

966
01:43:44,470 --> 01:43:52,600
And so all those relationships we've got with Caltech and with the team at Caltech within Genzer and the CPI have just blossomed,

967
01:43:52,600 --> 01:43:57,070
you know, and the lovely thing about all that is there's no paperwork.

968
01:43:57,310 --> 01:44:02,320
Nobody had to sign anything. We didn't have an MTA's, we didn't want an MTA, so we kept, you know,

969
01:44:02,590 --> 01:44:07,870
we didn't talk about it to the people who said, Oh, you need an MTA and that I've known an MTA take a year.

970
01:44:08,290 --> 01:44:13,500
And when the person who's going to do the work in the companies left because the MTA material transfer.

971
01:44:13,510 --> 01:44:16,930
Yeah. Yeah. It's all about secrecy. It's all nonsense.

972
01:44:17,290 --> 01:44:21,940
So lovely thing Ian said we're not doing any of that. We're just going to get on and do the experiments.

973
01:44:22,240 --> 01:44:26,649
And if we if we hadn't done that, we wouldn't be we certainly wouldn't have got funding.

974
01:44:26,650 --> 01:44:32,229
Funding from CEPI. No, this wouldn't have happened. So what's normal?

975
01:44:32,230 --> 01:44:37,120
And as it were, peace time where you could go through all this stuff and you think about the money you might

976
01:44:37,120 --> 01:44:43,420
make by having your spinoff company that will take over is just inappropriate for this setting.

977
01:44:43,690 --> 01:44:51,250
And I think we need to think very carefully about that, that this whole emphasis of spin offs and MTA fees and all this stuff,

978
01:44:51,820 --> 01:44:56,320
which costs a fortune, takes delays everything horribly,

979
01:44:56,500 --> 01:45:03,280
and basically generates mistrust at some level just in these settings needs there needs to be some

980
01:45:03,280 --> 01:45:09,309
legal way of throwing that one out of the window and and then perhaps picking up some pieces later.

981
01:45:09,310 --> 01:45:16,030
People won't. But because you've got to move, one thing you've got to do is you have to move fast and give them that.

982
01:45:16,030 --> 01:45:18,519
You, the Janet team moved very fast.

983
01:45:18,520 --> 01:45:24,489
They were ready because they've done all this stuff with these viruses and we have our differences with them over various things.

984
01:45:24,490 --> 01:45:33,670
But they did move very fast on this and expressing the glycoprotein in an anti virus, which is something, you know, that goes back 40 years really.

985
01:45:34,000 --> 01:45:38,649
They just did it and it worked and, you know, got on with it.

986
01:45:38,650 --> 01:45:43,270
And they deserve huge credit for pushing that forward.

987
01:45:43,360 --> 01:45:47,140
I think they haven't had enough credit for that, I think. But and they will.

988
01:45:48,070 --> 01:45:54,520
So yeah, it's it's being prepared and moving fast and you have to be able to do that and.

989
01:45:55,350 --> 01:45:58,620
So we're slow because we've taken ages to get to this point.

990
01:45:58,980 --> 01:46:04,210
But we hope that this might be a way of dealing with things in the future and.

991
01:46:05,950 --> 01:46:10,009
Um, but it's all it has been extremely interesting. And would I do it differently?

992
01:46:10,010 --> 01:46:18,669
You know, I think one thing that has happened is I thought I would never want to retire and I have to retire in a few weeks anyway.

993
01:46:18,670 --> 01:46:21,280
But I'm hoping to keep going emeritus.

994
01:46:22,000 --> 01:46:30,970
But I there were times and there have been times the first time in my life when I thought would be quite nice to wake up on Monday and just.

995
01:46:32,120 --> 01:46:36,050
Not have anything in the DA, you know, so.

996
01:46:37,600 --> 01:46:40,768
Lovely. Thank you very much. Lovely.