1
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Right. So could you just start by saying your name and your current position and affiliation?

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Yes. My name is William James. I'm professor of virology at the Sir William Dunn School of Pathology and a teacher in medicine at Prisoners College.

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Lovely. And without telling me your entire life story.

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But starting with how you first got interested in medicine, can you just give me your career highlights so far?

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Yes. Well, I studied Basic Biological Sciences as an undergraduate in Birmingham and was actually most interested in genetics,

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because genetics was a very strong subject there. And my my passion for doing research was ignited by getting a summer project.

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Um, uh, being offered a summer project while I was in Birmingham to work on was one of the lectures there on the genetics of control of bacterial,

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uh, differentiation. And I just became addicted to doing research myself and then doing a patient.

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It's natural thing to do. And there was a very prominent group in, in Oxford working on a related topic.

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And so I came to work with Joel Mandelstam in the biochemistry department on Bacillus, um, genetics then.

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And at the end of that Ph.D., which went quite well, um, I was offered a, uh, an academic post,

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temporary academic post in the Dunn School to teach the medical students bacteriology, which I foolishly agreed to do.

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And so I spent the next five or six, six years, I think, um, teaching the medical students bacteriology.

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That's what I paid to do. But I'm in the, uh, in the rest of my time, probably about three course of my time learning,

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uh, methods in molecular biology, monoclonal antibodies and virology.

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Importantly from James Porterfield, who was a great leader in the, um, in the, in the virus world.

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So that's how I got into viruses. And uh, after a fairly short time doing my own research on viruses, I decided that HIV,

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which is in the mid eighties, we talk about now, was the big topic to investigate.

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So I started working on HIV then and I cut a long story short.

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I carried on working on HIV for most of the rest of my career and the aspect that was the main focus.

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I had many little digressions, but the main focus has been how the virus infects one particular type of cell in the body called the macrophage,

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which is a coordinating cell in immune response and in tissue homeostasis.

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So that went very well. And we got to a point with those sorts of studies and the macrophage is a host for many other viruses as well, like dengue.

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And so. So what do the macrophages do? Well, macrophages.

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Well, they do sort of everything. They're macrophages or cells like macrophages.

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Been with us ever since we were sponges.

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You basically can't be a multicellular organisms without a little community policeman type cell like a macrophage,

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making sure there are no cells, being naughty and taking over the whole the whole body.

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In addition to which, they they gobble up foreign bodies, tidying them away and and any dead cells have to be there.

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And they encourage cells to grow when they need to grow and not when they don't.

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And all they specific are they know then that they're generalists.

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They've got a few tools in their in their in their bag, which enables them to recognise a bacterium or many sorts of viral patterns.

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But they, they're generalists in terms of antigens. They're not like lymphocytes that are able to recognise particular antigens.

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So as evolution went along and we got more and more complicated, the way we developed macrophages is also changed.

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So we now make macrophages as adults. Most of them we make from a blood cell called a monocyte,

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although they still are the residue of some of those most primitive type of macrophages in some of our tissues,

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like in the brain, indeed microglia of the brain,

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a type of macrophage that comes from that very early sponge sort of stage of of of macrophage biology.

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But because they are the sort of very mobile cell like amoeba, people remember what amoeba are like.

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They can move around. Unlike most body cells under their own power, they can hunt, seek out and destroy or what have you.

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So that makes them really very powerful and important in maintaining our tissues.

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And how do they interact with viruses? They interact with viruses in a number of ways.

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They've got a number of. Yes, there's quite a few ways they can interact with viruses.

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They've got a number of surface receptors that recognise certain common patterns

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in viruses which will enable them to hoover them up and and destroy them.

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Except, of course, it's the viruses evolved specifically to parasitised the macrophage and there are viruses that have have evolved to do that.

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And some of the, uh, viruses like Zika virus and dengue virus have, have indeed and been able to do that.

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And then inside the cell, they've got a lot of defence systems for recognising and responding to virus infection.

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So that's quite hard to infect as we'll maybe come up to a bit later of relation to SARS-CoV-2 for most non-specialist specialist viruses anyway.

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Long story short, the HIV experiments kept hitting a brick wall, which was a technical brick wall.

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But in order to really delve deeply into any particular aspect of the biology, of the interaction of the virus and the macrophage.

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So, for example. Sorry, I should just. Interject there that even in the modern era of well-controlled HIV infection,

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there is remains persistent infection of, for example, the microglia in the brain.

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And it's that that's responsible for some of the neurocognitive defects that you still see even in people controlling virus.

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So that's why it still remains important.

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But to try and study these processes really powerfully, we needed to be able to do modern molecular genetics on the cell as well as the virus,

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to test the hypothesis that Gene Product X was responsible for whatever the process was.

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And because macrophages have evolved to recognise any foreign DNA or RNA, you might throw at them as if it were a virus or a bacterium.

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It's extremely hard to do that. So about 15 years ago, I and my team developed a workaround for this a new methodology,

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starting with pluripotent stem cells, which means embryonic stem cells, and now these induced pluripotent stem cells.

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So these are non differentiated. So clearly undifferentiated induced to exactly develop different pathways.

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Exactly. They're undifferentiated human cells, which are normal genetically.

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So most of the cells people use in the abnormal genetic, they come from cancers.

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But these are normal, genetically undifferentiated. But we can monkey around with their genes.

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We're using clever techniques like CRISPR and so on, and then we can differentiate them down different pathways.

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And so we developed the macrophage differentiation pathway for these cells that

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many labs around the world now use and have used those tools in the HIV field.

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So you can just make macrophages. We can just churn out factories of macrophages, which is it's work much better than, frankly, I deserved.

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Well, sometimes one gets lucky and often one doesn't.

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That methodology has turned out to be terribly important, not only for the virus world, but also for the neurodegeneration.

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So we have quite a large program of collaborations with Alzheimer's and Parkinson's researchers,

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because a lot of what goes wrong in the brain turns out to be defects of the microglia that I mentioned before,

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failing to clear away the the things that accumulate with age and then getting

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overwhelmed by them and getting cross and then damaging the nerve cells.

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So there's been a big programme of work that Sammy currently in my lab leads on the neurodegenerative neuro inflammatory side of things,

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but I retain the focus on the virology aspects and of course is very big over continuing find this big overlap between the two.

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So that's that's where I was and to bring you up to about 2019.

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The big piece of work we were embarking on was indeed looking at how latency that is.

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The ability of virus to hide quietly inside microglial cells was regulated because if we could understand that, then we could stop it being a problem.

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And that was a quite ambitious program, but it all had to come to an end for reasons that probably are obvious to you.

81
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But we'll come on to that, that just kind of fill in your life story, as it were.

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And you you reached a senior position within the school, but also diverted into university administration.

83
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Oh, yes, yes. The dark side, as some people call it. Yes.

84
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Well, I think yes. What happened?

85
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The reason for this was quite a long process, some little tiny steps.

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So even in my very earliest days of my mid-to-late twenties as a junior academic in the dance school, um,

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there would be things that weren't working well for the department that I ended up getting the reputation of fixing,

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whether it was to do its computing systems or, or service systems or teaching systems or what have you.

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So finding solutions to those sorts of things turned out to be something.

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We like it then and, and then the financial systems was the next thing.

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And so after a while I was my role in some of that was a bit formalised by the then head of department,

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Herman Waldman, as what he'd like to call the departmental bursar.

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So we ran a very light ship administratively with me looking after the, uh, the financial strategy for the department and.

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And how it was run. And another colleague.

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Shona murthy looking after the human resources side of things.

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Otherwise we had some very, very able but quite junior finance officers and h.r.

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Officers to manage the day to day. That worked very well and I did quite enjoy that.

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Actually being able to sort things out as people seem to find difficult is always pleasurable.

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And the department did very well in that period on, on by various measures.

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And in that process I ended up. Fixing bigger issues, which ended up with building buildings.

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So I ended up developing one way or another for buildings on the done school site.

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Um, the three of them I took the lead on and the fourth one, the teaching centre was, I was just part of that of the team.

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But the first one was a single service building and I found that commissioning buildings

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to solve scientific challenges also interesting and that's been very satisfying.

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So if you can do things like that, then people ask you to do a bit more.

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And I was asked by Alistair Buchan to be his deputy when he was appointed head of medical sciences division, looking after the divisional level,

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the the financial challenges and the capital building, building challenges, and that that was quite satisfactory too.

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So I suppose the inevitable happened. Actually I had I had resisted this idea.

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I told him once before, under a previous Vice-Chancellor administration, I'd been tapped on the shoulder and said,

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Would I consider applying for TVC position or vice chancellor position?

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And at the time I said, No, I really don't want to do that sort of thing.

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I've got enough my hands full here doing my research and teaching, and that's what I would like doing.

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And I don't need to become full time in that. But about five years later, the the child was tapped again.

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And so I did apply and was appointed the pro vice chancellor by Andy Hamilton for planning and planning and resources,

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which is budgets and all that sort of stuff strategy.

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And so it's the equivalent that an American university would be provost.

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And on paper, that was absolutely perfect.

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The problem is in Oxford, and possibly not just Oxford, but in Oxford.

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Most of the job is not the technical, the logistics, the analytical,

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but it becomes more and more the higher and higher you go more about people management and politics management.

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So I don't think that was particularly my skill to them.

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So I achieved some of the things that I wanted to achieve, but some of the others were just a bit too intractable.

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And is that just because there is a certain degree of devolution within the

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university and that the technical challenges happen at divisional labs so many ways?

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Exactly like this diffusion of responsibility, which is a good thing. I don't know.

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I actually think that devolving responsibility to the lowest level sensible, that's called the subsidiary principle of subsidiarity principle,

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I think isn't it is a good thing in principle, but you do have to have some coordinating coherent structure within which those units work.

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Otherwise you're a bit like a, um, a battle fleet all sailing in different directions.

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You know, there has to be a degree of coherence and that balancing those two things has never been tackled

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constructively in Oxford in much the same way it hasn't constitutionally in this country either.

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Um, it's, it's too difficult problem, but it did mean that the sort of things that quite often became very controversial

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weren't really solvable at the university level or things that were soluble universally.

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Other people didn't want you to solve. So one way or another it was somewhat unsatisfactory.

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But when did you step down? So I did that until mid 2017.

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So I've been back at the bench with and the classroom for five years.

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Hm hm. Um. Because quickly does isn't it perception quickly.

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Um, but I haven't regretted that at all. I mean, there were obviously lots of opportunities because this is just how the world

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works to look at other positions in other universities or other organisations.

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And some of them are quite tempting on the face of it, and you don't like to be impolite and not look at them.

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But actually I did the right thing, I think.

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Well, I think so. And it gave you it must have given you an oversight of how the whole university works that you.

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Yes, I mean works in inverted commas, I think. Yes, yes, yes.

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How it goes along. So finally, let us let us get to go with the time just asking everybody this.

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Can you remember when you first heard that there was something happening in China that might be quite

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serious and affect us and and further how you might actually pivot your own research to address it?

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Well, I don't think. Can you be reliable? Yes, I well remember I was in the shower on a sunny Saturday when I heard somebody come on the radio.

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It was this growing awareness of some reports fairly early on in the beginning of 2020.

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I don't think I really was aware of it in the end of 2019, really, but they became very,

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very obvious very quickly that this was a problem like SaaS, but much worse.

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Do you have Chinese colleagues? I mean, yes. So I have colleagues both in Hong Kong.

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Well, in Hong Kong and in mainland China, in Shanghai and in Peking, some of which are some of whom I've worked on.

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So I was talking to them and um, yeah, the sense that this was a serious pandemic threat was we, we arrived at.

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I mean, I think the community arrived at very early, to be honest.

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In and within the first couple of months of the year. Easily, um, I think because it was clearly different from the original SARS virus in uh,

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I mean the key respect it was, it was that it would transmit without necessarily causing symptoms initially.

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Whereas with sars-cov-1 you got symptoms at the point you were very, very seriously ill and that was the first point to which you would transmit.

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So it was clearly a much greater threat,

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but we didn't know quite how much until it started spreading and then spread really rather rapidly, as you know.

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Um, so yes, it became very obvious by mid-February that this was something we were all going to have to take very,

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very and I know many other people were, were thinking hard about this as well.

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Um, it took a little bit longer for me decide whether that I should get involved because I've never worked on coronaviruses,

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as indeed many people haven't.

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But what I have done, um, was in some of those early things I talk about with those building projects, um, I have designed,

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commissioned and run containment laboratories for, um, dangerous pathogens for most of my career, which are, well, things like HIV, for example.

165
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No, I mean, sorry. Oh, containment, of course, is a place where you can safely work on nasty pathogens without them escaping.

166
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And imagine the sort of physical and procedural barriers you need to make sure that people don't take their work home with them accidentally.

167
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Um, so we were in a good position from that respect and it became very clear that nobody else in Oxford was in a particularly good position.

168
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Um, so we were the first to say, okay, right.

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Well, you're going to need some ability to work on real viruses.

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There's many experiments you can do that are useful in, in response to the pandemic that don't involve working on real infectious virus.

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And there were lots of labs doing that, but quite a few these lines of work like for example, the vaccine development stuff.

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If you don't have a test on real live virus, you can't proceed.

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And so that was what we were able to provide. It took quite a lot of, uh, well, a great deal of work for a few months.

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I think we were ready towards the end of March with a health and safety executive approval for working on SARS-CoV-2 and I and uh,

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uh, a research assistant called Becky Moore. I've interviewed her and interviewed her already, uh,

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did the lion's share of the work getting all that ready with lots of great support from our safety office,

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Tracey Muster and Safety Office and so she's on my list. A good I've got a date to talk to.

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Excellent. Excellent. Now, it was that there was, there was a lot of pulling together at that stage.

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I'm not sure that everybody around Becky and I, as it were in the department,

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generally understood quite how much work and is involved in putting this stuff together safely.

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But be that as it may, it came off.

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And of course, from around about Easter, the possibility of anybody in the department doing any work on anything else became minimal.

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So. So we were able to recruit to the call team, um, a bunch of, uh,

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graduate student postdocs that worked on other viruses and train them up to work on this.

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So after about three months, we, we were able to hand quite a lot of the experimental work on, onto,

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onto this team and um, and that was able to deliver for various, um, um, collaborating, uh, groups useful, um,

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useful analytical techniques, I guess the chief amongst which is something called the um,

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infectivity reduction neutralisation assay, which is basically a way of testing whether the, uh, antibodies present in a sample.

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It could be a human serum sample or it could be an experimental reagent with whether they are capable

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of preventing virus from infecting cells and quantifying how capable they were of doing that.

191
00:22:11,530 --> 00:22:15,250
Um, and did you need to use your stem cell technology?

192
00:22:15,490 --> 00:22:17,500
No, not for that. Not for that. No, not for that.

193
00:22:17,770 --> 00:22:27,250
We we have, um, I'll come onto that later because we have been using it for things that you otherwise can't do, which is a nice illustration.

194
00:22:27,610 --> 00:22:33,939
But for the standard neutralisation assays, there's a the world of virology is very conservative.

195
00:22:33,940 --> 00:22:39,010
And if we're very happy with a cell line called Villarosa, which comes from the African green monkey.

196
00:22:39,410 --> 00:22:46,600
Uh, um, uh, and if you're virus is able to grow in that cell, which this virus is,

197
00:22:47,740 --> 00:22:52,150
then people know what you're talking about when you say, I've done an infectivity assay in the cell line.

198
00:22:52,660 --> 00:22:59,260
Um, what we did have to develop so was a higher throughput method for doing that assay.

199
00:22:59,800 --> 00:23:11,080
Um, the assay we started with was the classic plaque assay, the, um, in exactly the form that was developed by James Porterfield back in the sixties.

200
00:23:11,080 --> 00:23:15,460
James Ford, who had been my mentor in virology and had done the school originally.

201
00:23:16,150 --> 00:23:23,830
Um, and it served us very well, but it wasn't terribly high throughput, so we could only assess the, uh,

202
00:23:23,830 --> 00:23:34,210
the neutralising power of a handful of reagents each week in order to, in that sort of assay because of the format.

203
00:23:34,820 --> 00:23:38,200
Um, so we were, we, we sat down and thought, well,

204
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can we make a higher throughput version looking at what other people had done in some other systems and with, um, uh, some, uh,

205
00:23:47,590 --> 00:23:54,540
reagents provided by Alan Townsend's group, uh, of particular, uh,

206
00:23:54,820 --> 00:24:05,650
human monoclonal antibodies which had been derived from patients in Taiwan and with some suggestions from Gavin's Cretans lab on,

207
00:24:06,220 --> 00:24:09,280
uh, work they had been doing already in dengue virus,

208
00:24:09,280 --> 00:24:16,820
we were able to develop what we call a micron neutralisation assay, which is about four times the throughput, um,

209
00:24:17,110 --> 00:24:22,800
in about a quarter of the times as a 16 times throughput, which enables us to,

210
00:24:22,860 --> 00:24:26,860
to screen a much larger number of things that is very technical and trivial sounding.

211
00:24:26,860 --> 00:24:35,380
But actually any of these things where you're wanting to see is something effect effective or not, you need to be able to test a lot of individuals.

212
00:24:35,680 --> 00:24:41,880
And so we were able to do that. So what were the kinds of question and well, actually ask another question first and then come back to that one.

213
00:24:42,430 --> 00:24:44,330
You used the word collaboration a little ago.

214
00:24:44,410 --> 00:24:52,389
Now you've talked about old and and so was there very much a sense of all the departments that were pulling together on this?

215
00:24:52,390 --> 00:24:55,540
And was that novel or have you always worked like that? Mm hmm.

216
00:24:56,290 --> 00:25:03,560
Um, I think for the first probably nine months, there was a unique sense of pulling together.

217
00:25:03,830 --> 00:25:09,760
I think after nine months, we went back to kind of normal levels of collaboration with a certain amount of competition as well.

218
00:25:10,330 --> 00:25:17,290
But for the for the first period, it was very, very clear, everybody setting aside everything just to make sure things happened.

219
00:25:17,740 --> 00:25:19,389
Um, so, for example,

220
00:25:19,390 --> 00:25:29,350
we hosted in our containment laboratory suite several other groups from other departments around Oxford until they had the capacity to,

221
00:25:29,350 --> 00:25:31,750
to, to, to do things themselves.

222
00:25:32,350 --> 00:25:43,870
Um, and yes, there was a very useful forum that Richard Cornell, uh, convened, which was weekly to start off with, um, of,

223
00:25:44,230 --> 00:25:52,630
of a round robin all on teams or zoom one on one together where all the people working in the relevant areas would report any,

224
00:25:52,990 --> 00:25:56,620
um, any progress or any challenges or what have you.

225
00:25:56,620 --> 00:26:01,749
And we shared a great deal of, of expertise and information and, and support that way.

226
00:26:01,750 --> 00:26:09,130
And that was, that was very, very valuable and quite, quite cheering that, that, that, that happened so readily.

227
00:26:09,610 --> 00:26:13,720
Um, obviously you can't keep up that level of intensive.

228
00:26:13,950 --> 00:26:17,190
Of of of networking for ever.

229
00:26:17,670 --> 00:26:30,480
Although I'd have to say that the the change is that the lockdown imposed restrictions on travel have been incredibly beneficial, in my view,

230
00:26:31,380 --> 00:26:38,220
in forcing us all around the world to use these systems like Zoom and teams more to have

231
00:26:38,220 --> 00:26:42,900
meetings quite often almost at the drop of a hat with people from all around the world.

232
00:26:42,900 --> 00:26:53,850
And that's very, very useful. So one particular one I'm on is a W.H.O., one that meets every month and shares experience and and technology and so on,

233
00:26:53,850 --> 00:26:55,919
all about these sort of diagnostic assays.

234
00:26:55,920 --> 00:27:02,800
And I was I was talking there and that wasn't happening before because you had to be in Washington to go to Geneva to,

235
00:27:02,930 --> 00:27:06,690
to be part of those sort of things. And I think that's great actually.

236
00:27:07,740 --> 00:27:10,830
Um. Yeah. So that's, that's good.

237
00:27:11,160 --> 00:27:20,490
Obviously, there's still a lot of collaboration. I mean, this, the, the projects that run through my own group as suppose sort of in the facility, um,

238
00:27:21,510 --> 00:27:25,800
with lots and lots of groups in my own group involve collaborations with um,

239
00:27:26,580 --> 00:27:34,229
several groups in MDM and at Harwell and in China and in Colorado and so on.

240
00:27:34,230 --> 00:27:40,049
So it's a highly collaborative thing, but that's only slightly more so than normal, as it were.

241
00:27:40,050 --> 00:27:46,140
At this point. They're generally two way or sweet way collaboration on focus particular projects.

242
00:27:47,390 --> 00:27:50,580
Um, so what were the urgent questions that needed answering?

243
00:27:50,640 --> 00:28:00,480
Yeah. So the, the, I guess the two, um, the two that we got involved in early on, the less famous of the two I'll,

244
00:28:00,600 --> 00:28:06,890
the most famous of the two, first of all, was a real challenge that they had in the, um,

245
00:28:07,020 --> 00:28:15,670
in the hospitals and the diagnostic branches of hospitals and knowing how safe it was to handle patient samples, um,

246
00:28:15,690 --> 00:28:25,740
because this virus isn't all that unusual, but in this virus, you can have samples that are positive for the presence of viral components.

247
00:28:27,240 --> 00:28:30,630
But should you be handing them as if they really are containing infectious virus?

248
00:28:30,870 --> 00:28:34,799
Because if you handle them like that, then you have to handle them in a facility like ours,

249
00:28:34,800 --> 00:28:38,580
which is incredibly constraining, and you can't run lots of diagnostic tests.

250
00:28:38,970 --> 00:28:51,270
So we helped them out in doing some systematic evaluations of such samples with different levels of evidence of, of uh, viral components in them,

251
00:28:51,930 --> 00:28:59,490
and were able to show that for the vast majority of them, unless you've got extremely high levels of viral components in there,

252
00:28:59,760 --> 00:29:08,819
what was their was not infectious, it was merely junk and could be handled under good laboratory practice conditions in

253
00:29:08,820 --> 00:29:12,930
the standard diagnostic lab which enabled them to these are mostly blood samples,

254
00:29:12,930 --> 00:29:20,280
blood samples and generally blood samples. And in fact, it's been very hard to find any infectious virus in things like blood.

255
00:29:21,090 --> 00:29:30,360
Yeah. Other than in upper respiratory tract secretions you can find you got plenty of evidence of viral components, lots of it in the gut.

256
00:29:30,360 --> 00:29:33,749
For example, very hard to isolate an infectious virus.

257
00:29:33,750 --> 00:29:37,110
We don't we still don't understand this. This has been a bit of a puzzle for a couple of years.

258
00:29:37,560 --> 00:29:46,290
Um, but, but the infectious virus is by and large, what's coming out in the aerosols from, from people's noses.

259
00:29:46,290 --> 00:29:49,590
And that's so that was helpful, I think.

260
00:29:50,190 --> 00:30:01,020
Um, and the second thing obviously was the, the famous face to, uh, clinical trial for what became the AstraZeneca vaccine where um,

261
00:30:01,770 --> 00:30:13,589
that the Oxford team had some results from a couple of collaborators outside Oxford on some early samples that they weren't very happy with.

262
00:30:13,590 --> 00:30:18,480
Uh, but there were reasons for not being happy with the results was sound.

263
00:30:18,810 --> 00:30:26,160
So they asked us if we do a comprehensive set of, of tests of uh, neutralising assays on these samples, which we did.

264
00:30:26,940 --> 00:30:38,819
Um, that was quite interesting experience in that, um, it didn't really strike me and the team when we started doing it,

265
00:30:38,820 --> 00:30:47,920
but we were at the point of being about to reveal the results is on the last,

266
00:30:48,270 --> 00:30:56,459
on the homestretch when we suddenly sort of realised um, this is quite a high um, consequence experiment.

267
00:30:56,460 --> 00:31:09,000
If what we discover is that the people that have had uh, the vaccine do not have neutralising antibodies at a sufficiently high titre in their blood,

268
00:31:09,660 --> 00:31:13,670
this is going to be a no go result, because there's no way of.

269
00:31:13,710 --> 00:31:16,590
Get permission to a large phase three trial.

270
00:31:17,070 --> 00:31:22,920
If you're not generating the thing that's known to be the protective thing, which is neutralising antibodies.

271
00:31:23,820 --> 00:31:30,990
Luckily we didn't know what the samples were. They were all under code, which is always a great relief actually when people send you stuff on a code.

272
00:31:31,470 --> 00:31:37,290
But we got, we got the answers that we sent back to the, uh, the gener uh,

273
00:31:37,320 --> 00:31:44,340
and they decoded them and analysed them and luckily it corroborated what they were hoping to see,

274
00:31:44,340 --> 00:31:47,490
which was, uh, that the, the, the, um,

275
00:31:48,390 --> 00:31:55,709
the adenoviral vectored vaccine was indeed able to elicit good neutralising responses in almost all participants.

276
00:31:55,710 --> 00:31:59,670
So yeah, that was, that was, that was good, good thing to have done.

277
00:31:59,910 --> 00:32:07,080
And we were able to round quickly and uh, and then the whole string of things after that of various monoclonal antibody reagents and,

278
00:32:07,080 --> 00:32:12,750
and aptamer reagents and nanobodies and chimeric proteins and all sorts of other things that I think we need to go into those.

279
00:32:13,070 --> 00:32:21,380
Well I'm happy to talk about this. Yes. So the point of those was the point of those to start thinking potentially about therapy.

280
00:32:21,390 --> 00:32:24,990
Absolute. Yes, yes. Yes. Therapy and and analysis, essentially.

281
00:32:24,990 --> 00:32:34,320
Yes. So, um, you'll be aware of monoclonal antibodies that are used in therapy, so the Regeneron antibodies and that sort of thing.

282
00:32:35,670 --> 00:32:45,389
Um, uh, but of course making antibodies is and infused image people's arms is, is not the sort of thing that you can do at the drop of a hat.

283
00:32:45,390 --> 00:32:56,790
So millions of people are in fact around the world. So the hunt has been on to try and find some better way of doing that.

284
00:32:57,120 --> 00:33:03,270
More, uh, that's either cheaper or more powerful or easier to administer.

285
00:33:04,290 --> 00:33:09,420
And actually more recently we'll come back to this stuff that you might do that you could keep on the shelf for future pandemics.

286
00:33:12,180 --> 00:33:21,330
And so collaborators of a variety of in a variety of places had their pet approaches to doing this.

287
00:33:21,360 --> 00:33:30,189
Um, I have my pet budget. I might talk about it in a moment. Um, uh, but we evaluate them all in the same system.

288
00:33:30,190 --> 00:33:32,909
This is quite critical to be able to evaluate them all against each other.

289
00:33:32,910 --> 00:33:43,799
So, um, uh, give you the simple example is, um, human antibodies derived from, for example, AIDS patients in Taiwan.

290
00:33:43,800 --> 00:33:47,430
And we were able to show which ones were neutralising, which ones weren't,

291
00:33:48,300 --> 00:33:55,950
which ones neutralised, um, what turned out to be, uh, variant, invariant bits of the virus.

292
00:33:55,950 --> 00:34:05,130
In other words, would they survive the changes that the viruses evolved over the course of the, of the pandemic in advance of concern?

293
00:34:06,390 --> 00:34:07,230
That's fairly simple.

294
00:34:07,230 --> 00:34:18,000
One and another reasonably simple one is make is, uh, colleagues, um, uh, making versions of the virus receptor, the ace2 receptor,

295
00:34:18,450 --> 00:34:28,650
um, usually fused to, um, the back end of an antibody molecule so that there is now a soluble but dimeric, um, version of itself.

296
00:34:29,400 --> 00:34:41,070
Um, and using this as a decoy essentially, uh, and what one, the advantage of that, um, would be that the virus has no where to evolve to with that.

297
00:34:41,070 --> 00:34:49,350
If the virus is no longer blocked by that, then the virus can presuming not interact with the same molecule on the host surface and infect cells.

298
00:34:49,350 --> 00:34:53,430
So that's a that's a bit of a clever block.

299
00:34:54,630 --> 00:35:01,290
The problem with that one has turned out to be that the level of potency isn't sufficiently high.

300
00:35:01,560 --> 00:35:04,950
So it's very, very resilient to change, but it's not very potent.

301
00:35:04,950 --> 00:35:08,729
And this is quite a case. It's it's catching some of the virus, but not enough.

302
00:35:08,730 --> 00:35:16,140
This it you have to have a very, very high concentration of your your inhibitor to be a be a good block, effective block.

303
00:35:16,350 --> 00:35:28,290
And that's a problem. And this has been quite a common thread that things that are potent, uh, are generally very sensitive to virus mutations.

304
00:35:28,290 --> 00:35:31,769
Things that are resilient to virus mutations tend to be not very potent.

305
00:35:31,770 --> 00:35:35,370
And that's been a, that's been a very common, not universal threat.

306
00:35:36,330 --> 00:35:37,170
But this is a yeah,

307
00:35:37,170 --> 00:35:47,360
I think there's a little bit of immunology we haven't quite tied down the when you say the things that are potent and are sensitive to mutations.

308
00:35:47,400 --> 00:35:56,309
Yes. Saying is that the you start off with a nice lock and key, but the virus works out how to rearrange itself a bit.

309
00:35:56,310 --> 00:35:59,430
Exactly. And particularly despite the spike protein. Yeah.

310
00:35:59,610 --> 00:36:05,309
Yeah. We if you'd like to dive into that a little bit, I'm very happy to talk about that because this is obviously quite a bit of what the the more

311
00:36:05,310 --> 00:36:08,910
basic stuff we've been doing has been trying to understand all these all these changes.

312
00:36:08,910 --> 00:36:13,620
So, yes, why this the spike is the is the surface protein of the.

313
00:36:13,680 --> 00:36:20,430
Virus, which the virus deploys to bind first to its receptors and then to fuse with the cells to gain entry.

314
00:36:22,380 --> 00:36:25,770
The spike of SARS-CoV-2 is Trimeric molecule.

315
00:36:25,770 --> 00:36:28,140
Like, um, like any corona virus.

316
00:36:28,680 --> 00:36:39,900
It has a couple of knobs on the surface of each component of that trimer, um, one of which is known to most people as the receptor binding domain.

317
00:36:40,140 --> 00:36:45,690
RBD And that is the bit that interacts with the ACE2 receptor.

318
00:36:46,230 --> 00:36:53,690
Um, uh, I think Alan Townsend came up with a very memorable picture of this one, which I like and I always use.

319
00:36:53,700 --> 00:37:00,030
So if you imagine the form of a little squirrel, cute little squirrel, just nibbling away at nuts like that on your lawn.

320
00:37:00,120 --> 00:37:06,090
And I think he was looking at his and doing all such things. That's what this RBD looks like.

321
00:37:06,690 --> 00:37:14,790
Yeah. Through a slight squint, um, when it's standing upright, but it is normally not standing upright is normally sleeping on its left hand side.

322
00:37:14,790 --> 00:37:23,640
So the three little squirrels all sleeping on the left hand side, and every so often one pops up and it's only in the pop up version that it can bind.

323
00:37:23,880 --> 00:37:27,990
So it sort of is, and back to the ace2, uh, molecule.

324
00:37:28,980 --> 00:37:35,040
And then once that's happened, it's stuck in there, it's locked if you like, and then the other ones can pop up as well.

325
00:37:35,040 --> 00:37:42,690
And once to have popped up and they're locked, then the third one almost inevitably goes in fusion reaction takes place, right?

326
00:37:43,830 --> 00:37:50,580
So the bits of the squirrel, the sort of back of the head and the back that interact with a tune,

327
00:37:51,330 --> 00:37:56,070
um, have to be pretty invariant, otherwise it can't bind to waste to any longer.

328
00:37:56,820 --> 00:38:08,460
And in principle, those are good sites for antibodies to bind because if an antibody binds to their, then it should be resistant to mutation.

329
00:38:09,270 --> 00:38:18,599
That hasn't actually proved to be the case generally because many of the variants of concern have found

330
00:38:18,600 --> 00:38:25,230
mutations that manage to preserve the Ace2 interaction but disrupt the most common antibody interactions.

331
00:38:26,370 --> 00:38:31,709
And was that a puzzle? When you say it was a puzzle for people until until a lot of the structural biologists,

332
00:38:31,710 --> 00:38:41,940
people like Dave Stewart and folks in the US and everywhere else start to actually work out exactly how these things are binding.

333
00:38:42,420 --> 00:38:47,490
But it just shows you how multi clever viruses as it shows you how clever Darwin is, you know, just.

334
00:38:47,790 --> 00:38:59,280
Yeah. And of course. The fact that out there with millions of people, viruses being exposed to human antibody all the time,

335
00:38:59,700 --> 00:39:05,550
there's a very strong selection pressure for viruses to evolve, resistance to antibodies.

336
00:39:06,450 --> 00:39:14,310
So I maintain their ability to bind ways to so the numbers are against us in that respect.

337
00:39:14,910 --> 00:39:20,340
Now, recently there have been a couple of reports of monoclonal antibodies,

338
00:39:20,340 --> 00:39:27,030
very rare ones binding to sites on the squirrel, which generally at the squirrel's lair,

339
00:39:27,030 --> 00:39:34,259
if I can put it that in a delicate, uh, delicate way, which overlap with the bit by so ace2,

340
00:39:34,260 --> 00:39:38,459
but only slightly but are very, very conserved between all these various control.

341
00:39:38,460 --> 00:39:42,450
And those are potentially more, more powerful therapeutics.

342
00:39:43,830 --> 00:39:51,180
So yes, so I'm indicating that all of the use when you trust the antibodies, bind to the squirrel on top is not quite true.

343
00:39:51,190 --> 00:39:57,299
There are antibodies to bind. For example, down on the flanks of the squirrel that neutralise.

344
00:39:57,300 --> 00:40:05,250
But generally they don't neutralise as well, but they often more resistant to mutation because this is not so subject to selection.

345
00:40:05,550 --> 00:40:14,070
There are indeed sites further down the spike that are able to be bound by antibodies that can utilise mice,

346
00:40:14,070 --> 00:40:17,520
but they're much rarer to find those antibodies.

347
00:40:18,060 --> 00:40:22,920
They didn't come up as often. But it's that squirrel.

348
00:40:23,760 --> 00:40:29,730
It's very good image, isn't it, in um, uh, the Swedish.

349
00:40:29,740 --> 00:40:34,680
So, so the question then is can we find clever alternative ways to regular antibodies to,

350
00:40:35,370 --> 00:40:40,800
to, um, to, to, to neutralise spike by binding to the right bits of squirrel.

351
00:40:42,450 --> 00:40:45,450
Um, uh, sounds like Friday night tennis, doesn't it?

352
00:40:45,450 --> 00:40:55,650
Nice bit of squirrel. Um, so the ace2 dimer was obviously one one way, but just not, uh, uh, potent enough.

353
00:40:56,130 --> 00:41:07,500
Um, colleagues in, uh, in, in Zhuhai, in, um, in, in China near Hong Kong, um, uh, ex Dan School, um,

354
00:41:07,920 --> 00:41:14,250
came up with a chimeric version which had an ace two component and an antibody component in one molecule.

355
00:41:14,700 --> 00:41:22,950
Uh, the idea of there being I bind two different sites on the spike, uh, uh, I can triangulate the virus and give it know where to go.

356
00:41:23,190 --> 00:41:28,920
We published that one and it did indeed neutralise, but that hasn't gone into clinical trial.

357
00:41:30,250 --> 00:41:38,280
Um, uh, colleagues at the Rosalind Franklin Institute, um, uh, to nanobodies.

358
00:41:38,670 --> 00:41:45,690
Uh, so these are from llamas which aren't, but which are like our regular antibodies.

359
00:41:45,690 --> 00:41:50,850
But they have a, just a single domain as opposed to double domain binding to the antigen.

360
00:41:51,270 --> 00:41:58,979
Uh, which has some advantages. And so we were able to help them find, identify which ones were neutralising their very powerfully.

361
00:41:58,980 --> 00:42:07,470
Interestingly, we published quite a few papers on those now I think, and it's those that are the subject of a Wellcome Trust collaborative program

362
00:42:08,910 --> 00:42:17,040
for finding such molecules that would target multiple different viruses that,

363
00:42:17,340 --> 00:42:22,200
you know, disease X the the next ones that might breakthrough and to have not just multiple

364
00:42:22,200 --> 00:42:25,439
distant coronaviruses but not well we could start with the Corona virus,

365
00:42:25,440 --> 00:42:28,020
but we're also interested in Nipah virus and other things as well.

366
00:42:28,830 --> 00:42:40,260
Um, so the challenge there is to see if we can, if we can make such things, if they can be good, resilient, cheap, storable, almost.

367
00:42:40,380 --> 00:42:45,660
So that gives you a first line of attack when a new pandemic starts.

368
00:42:45,840 --> 00:42:49,140
So what do you call that to that? It's not it's not exactly a vaccine.

369
00:42:49,230 --> 00:42:55,709
No, it's not a vaccine. It's was it's almost like passive immunisation, which is it used to be a thing, but it's not with antibody,

370
00:42:55,710 --> 00:43:00,790
but it's this is the equivalent of that is prophylactically using that that the,

371
00:43:00,810 --> 00:43:09,810
uh, um uh a antibody like but you would, you would inject it in advance of a exhort the academic colleagues other than to patients.

372
00:43:09,840 --> 00:43:17,610
Exactly. And it would give you in that window before even though we've got accelerated vaccine development, there's that period isn't there.

373
00:43:19,470 --> 00:43:22,080
Even if that period is much shorter than we ever thought it could be,

374
00:43:22,500 --> 00:43:30,960
it's nine months or something that was in that first six months or so to have something that you could use just to slow the wretched thing down.

375
00:43:31,140 --> 00:43:40,170
Other than telling people to stay indoors. So that's, that's the idea behind that sort of approach.

376
00:43:41,070 --> 00:43:48,060
Um, of course having to inject something is, as we indicated earlier, not ideal.

377
00:43:48,690 --> 00:43:52,500
Um, you'd really rather have something that I think is a.

378
00:43:52,590 --> 00:44:00,210
Hill or more easily to envisage take in the form of a Zoom inhaler or something like that.

379
00:44:00,420 --> 00:44:04,710
It didn't require medical interventions and so on.

380
00:44:05,490 --> 00:44:14,490
So we've also been working with um, uh, a company in Colorado on a different approach.

381
00:44:14,940 --> 00:44:19,139
And this is making what's called abstinence, which is a completely different sort of chemistry to,

382
00:44:19,140 --> 00:44:24,180
to any of the antibodies or nanobodies or chimeric proteins that I've been speaking about,

383
00:44:24,830 --> 00:44:37,170
uh, but have similar properties in that they, they are, you can isolate, um, atoms and they are the bits of protein.

384
00:44:37,170 --> 00:44:42,510
They know they're nucleic acids, they're modified, they're non-natural nucleic acid.

385
00:44:43,140 --> 00:44:46,350
And the beauty of them is it's really hard to describe this.

386
00:44:47,100 --> 00:44:50,250
Does this have to be good for a generalist audience generally?

387
00:47:09,250 --> 00:47:17,350
Um, and so at the they were in the same position as any lab in the UK was that they

388
00:47:17,350 --> 00:47:21,790
were told they couldn't do their usual stuff at the beginning of the pandemic,

389
00:47:22,180 --> 00:47:26,260
but if they had any SARS-CoV-2 projects, they could go in and do that.

390
00:47:26,920 --> 00:47:35,709
So I approached them and said, Why don't we do this thing like we did for HIV before and make an app to as to the cells, the surface protein of cells.

391
00:47:35,710 --> 00:47:39,760
CO two And you guys are the best in the world at doing that.

392
00:47:39,910 --> 00:47:43,809
After the selection and leave, they jumped at it. And so, so we did that.

393
00:47:43,810 --> 00:47:47,110
And the paper's not out yet. I hope it'll come out soon.

394
00:47:47,760 --> 00:48:02,260
Um, but we were able to find some, uh, extraordinarily powerful, very small actors that neutralise more potently than any antibody we've yet found.

395
00:48:02,770 --> 00:48:07,210
Neutralises monomers. Not that you don't have to have them as dimers. That's something you can come back to if you like.

396
00:48:07,830 --> 00:48:16,300
Um, and a very, very much cheaper and more robust and completely resilient to all the variants we've yet seen in the virus.

397
00:48:16,630 --> 00:48:20,500
And they bind in the rear of the squirrel as well.

398
00:48:21,250 --> 00:48:24,700
Um, so you've done the neutralising, I've done the neutralisation stuff.

399
00:48:24,700 --> 00:48:31,570
And, and, and Jan in turn in Alan's lab has done the competition, realises to show that their binding to the rear of the squirrel.

400
00:48:33,340 --> 00:48:38,930
Um, so those chemicals are as cheap as chips to make.

401
00:48:39,310 --> 00:48:45,850
Um, the. There's been a real revolution. Well, of course you've come across the, the RNA vaccine stuff.

402
00:48:46,840 --> 00:48:50,559
Nucleic acid like that can be made on a vast scale, really cheap.

403
00:48:50,560 --> 00:48:55,180
In fact, these ones can be made even more cheaply than that on a large scale.

404
00:48:55,930 --> 00:49:04,180
And because they're not proteins, um, because then so nucleic acids, they are, they're very much more stable.

405
00:49:04,180 --> 00:49:10,870
You can, you can leave them in a solution at room temperature for weeks and weeks and weeks and they just don't degrade.

406
00:49:10,870 --> 00:49:15,190
You can leave them as a dry powder in a vial on a shelf, even in a tropical country.

407
00:49:15,460 --> 00:49:19,330
And they will stay perfectly open to the time where you need to reconstitute them.

408
00:49:19,690 --> 00:49:29,680
So we hope where we're hoping to go. And uh, actually, um, this isn't breaking confidence, but the Gates Foundation has asked us to,

409
00:49:29,710 --> 00:49:39,700
to pursue this is to formulate these things in a clinically useful way in, for example, inhalers.

410
00:49:39,700 --> 00:49:48,910
And so to to try and get them to the point where we could have them sitting on shelves, formulated off the shelves so they can be sold the boots.

411
00:49:49,330 --> 00:49:56,630
Yeah. And you can imagine I think much more easily going to your, um, your bathroom cabinet once a day,

412
00:49:56,680 --> 00:50:03,400
taking a puff of your inhaler to protect your upper respiratory tract for the rest of the day.

413
00:50:03,520 --> 00:50:08,440
Then you can going in once a week and having an infusion of antibody in your in your arm.

414
00:50:09,520 --> 00:50:13,020
So that's the idea with those. And I think as we did clinics.

415
00:50:13,170 --> 00:50:18,130
Mm hmm. Yeah. Thanks. I think I've got I've got to excited that I'm sorry.

416
00:50:18,460 --> 00:50:23,170
Of, of, of the crisis. So is that the thing that you said earlier?

417
00:50:23,170 --> 00:50:26,320
It was the thing that you were excited about that you were going to talk about later?

418
00:50:26,800 --> 00:50:30,430
Sorry. It probably was. It probably was.

419
00:50:30,460 --> 00:50:36,310
Uh, yeah. So the other thing you mentioned you were going to come back to later was ways of using the stem cells.

420
00:50:36,400 --> 00:50:44,870
Oh, yes, yes. And this is where we get to more of the biological side of the virus.

421
00:50:44,870 --> 00:50:48,990
So obviously, um, we can study how virus infects us.

422
00:50:49,210 --> 00:50:55,120
Model cell lung like a virus cell. But it's, it's in principle entirely possible,

423
00:50:55,150 --> 00:51:01,090
more than possible that the consequences of virus infecting virus so different from the consequences of virus infecting a,

424
00:51:01,090 --> 00:51:03,940
uh, human respiratory epithelial cell.

425
00:51:04,270 --> 00:51:09,280
If anything else, the reason why we have various cells is and why they're so useful is they have no interference system.

426
00:51:10,450 --> 00:51:18,790
So whereas you do y so the closer you can get to a cell that's like the cell of your respiratory epithelium, the better.

427
00:51:19,870 --> 00:51:28,480
And up till now, the only source of such cells has been biopsies from people's bronchi.

428
00:51:29,170 --> 00:51:34,239
And these are available, but only very small quantities and and and not routinely.

429
00:51:34,240 --> 00:51:39,610
And of course, every donor has a different genetic background and small quantities.

430
00:51:39,970 --> 00:51:47,709
So what we've done, we didn't invent these methods, we're trying to improve on them is use the methods of pluripotent stem cell differentiation

431
00:51:47,710 --> 00:51:53,290
in vitro with and we succeeded in doing that to generate a respiratory epithelia.

432
00:51:55,000 --> 00:51:58,120
So these are the cells that line your windpipe exactly.

433
00:51:58,210 --> 00:52:03,430
When in fact there are two there are two major classes of these and I've learnt a lot since I've been doing this.

434
00:52:03,430 --> 00:52:08,800
I knew nothing about these sorts of cells at all before the cells that line your airway.

435
00:52:08,810 --> 00:52:13,000
These are ciliated is a ciliated epithelium.

436
00:52:13,070 --> 00:52:21,770
But this is a little here's the wave activity ways and so that's so the cells that have those waving pores, if you like,

437
00:52:22,190 --> 00:52:31,879
and cells that secrete mucus and what they're doing between them is is covering your that upper respiratory

438
00:52:31,880 --> 00:52:36,050
epithelium with a layer of mucus which traps things that you don't want to get into your lungs.

439
00:52:36,380 --> 00:52:39,830
And there's what's called the mucus ciliary escalator.

440
00:52:40,070 --> 00:52:42,590
Which way washes it up, up, up.

441
00:52:42,590 --> 00:52:48,440
Your response to treat until it gets to your swallowing bit where you swallow down your stomach and it gets all destroyed,

442
00:52:48,440 --> 00:52:55,540
all the mosaic is destroyed. And that's quite a complicated epithelium, but we can just about make that nowadays.

443
00:52:55,790 --> 00:53:00,740
Um, and that's where many of the viruses like to replicate.

444
00:53:01,400 --> 00:53:06,080
But there's another epithelium which is on the lining of the air sacs and varies by surface area.

445
00:53:06,080 --> 00:53:07,880
If you spread it is much more of that.

446
00:53:10,400 --> 00:53:16,670
The alveoli, the alveolar, obviously the more I've learned about them, the more amazing I find them to be as well.

447
00:53:17,060 --> 00:53:19,160
So they don't really have very, very thin cells.

448
00:53:19,200 --> 00:53:30,380
Type one side is a very, very thin cell which forms the the wall of this layer sac and allows gas exchange with between the air on the inside,

449
00:53:30,390 --> 00:53:38,420
the wireless and the contents of the blood on the other side. They are maintained by two other cells in them.

450
00:53:38,780 --> 00:53:43,730
So there's a type to numerous site which is the parent of the type one.

451
00:53:43,740 --> 00:53:48,890
So type one is like the in differentiated cell and they have a limited life and then they're gone.

452
00:53:49,740 --> 00:53:59,390
The type two is the tissue specific stem cell, which divides makes more type one tumour sites and also has various other functions like pumping,

453
00:53:59,930 --> 00:54:11,299
like any liquid that leaks into the virus back into the bloodstream. Um, so we can make those as well there they come in the differentiation pathway.

454
00:54:11,300 --> 00:54:18,350
They, uh, they're similar up to a certain point and then they, then they diverge so we can make both of these types of epithelia.

455
00:54:18,860 --> 00:54:27,800
And what's quite interesting is that different variants of different severity of virus infect preferentially one or the other.

456
00:54:28,490 --> 00:54:33,980
So most of your unpleasant symptoms come from if viruses managed to infect your RV only,

457
00:54:34,730 --> 00:54:40,760
whereas viruses that don't do that very well but managed to infect the upper respiratory tract are generally nicely transmissible,

458
00:54:40,760 --> 00:54:48,050
but not generally quite so dangerous. So your really serious diseases generally are lung diseases in the alveoli.

459
00:54:48,890 --> 00:54:56,360
So we've been able to do that and uh, the virus does what you'd hope it would do and was true for flu virus.

460
00:54:56,360 --> 00:55:01,700
We knew from others before it will replicate only infects cells from the surface,

461
00:55:01,700 --> 00:55:05,989
the apical surface, as opposed to the basso lateral surface from the other side.

462
00:55:05,990 --> 00:55:09,890
So the apical service is into the airway and the basement was into rest of the body.

463
00:55:10,910 --> 00:55:16,460
The virus infects itself, that side replicates, exits, just the same side goes out the way it came in.

464
00:55:17,030 --> 00:55:21,679
So they really do behave like the cells of your have your body.

465
00:55:21,680 --> 00:55:32,030
So we're trying to study the infection pathway in these cells and we've identified, um, a, uh, um, a,

466
00:55:33,140 --> 00:55:39,680
an enzyme controller of the traffic is normally present in these cells that controls

467
00:55:39,680 --> 00:55:43,010
the traffic of all the vehicles in and out of various compartments in the cell,

468
00:55:43,370 --> 00:55:48,649
which if you modify its activity, modify as far as replication very considerably.

469
00:55:48,650 --> 00:55:57,979
So we think we might be on the the early stages of identifying a new therapeutic target for response to infections.

470
00:55:57,980 --> 00:56:00,740
But there's a long way to go yet, but you can only do it in these sorts of cells.

471
00:56:01,250 --> 00:56:05,570
You can't do it in a undifferentiated pack of jelly like a virus cell.

472
00:56:07,010 --> 00:56:15,589
And the second thing that we're interested there is in how the biology of these cells is affected by the presence of the macrophages,

473
00:56:15,590 --> 00:56:23,450
which are also present in these tissues. So obviously there's the alveolar macrophage and there's an interstitial macrophage in the upper airways.

474
00:56:24,050 --> 00:56:32,120
And we know already from work we've done, others have done that the macrophages are very, very resistant to being productively infected by virus.

475
00:56:32,120 --> 00:56:36,530
They'll take up virus, but they really won't be producing any measurable amount of virus.

476
00:56:37,220 --> 00:56:43,620
What we don't yet know is. With their presence at the same time as these very susceptible cells,

477
00:56:44,010 --> 00:56:49,730
do they pass on the infection to these susceptible cells or do they protect their cells or what happens?

478
00:56:49,740 --> 00:56:53,130
And that's the that's the other big area of interest in our lab.

479
00:56:53,500 --> 00:57:02,829
Mm hmm. Yeah. So, I mean, I suppose when all this started, the level of knowledge of SARS-CoV-2 was just very, very low.

480
00:57:02,830 --> 00:57:06,180
I so you have to find out pretty much everything. Yeah. Yes.

481
00:57:06,360 --> 00:57:11,099
And it's it's it's been the case, I think, in science generally,

482
00:57:11,100 --> 00:57:17,910
that if there's a lot of attention on one in box virus, you get to find out a lot about it.

483
00:57:18,210 --> 00:57:23,070
Whereas if there's a rather obscure virus like frankly, the other coronaviruses were rather uninteresting.

484
00:57:23,070 --> 00:57:30,180
They didn't kill people, you know, we didn't know them about them before we get them that fresh.

485
00:57:30,180 --> 00:57:36,629
This flu is very often a corona virus, you know, the one that regulates clockwork sometime in the early Michaelmas term.

486
00:57:36,630 --> 00:57:41,970
I catch from my new students. Um, but it's not very serious.

487
00:57:42,750 --> 00:57:48,450
Uh, whereas this one was it. So a lot of lot of people around the world, thousands of researchers have been working on this,

488
00:57:48,450 --> 00:57:52,020
and we're finding out a great deal more than ever we knew before, which is a good thing.

489
00:57:52,050 --> 00:57:57,540
I think it was the same with HIV. People had a lot more HIV than we've known about retroviruses before.

490
00:57:57,540 --> 00:58:01,710
So that is, of course, the frustrating thing.

491
00:58:02,220 --> 00:58:09,570
The other flipside of that is highly competitive areas like that with lots of work and there's only a certain number of obvious questions to work on.

492
00:58:09,570 --> 00:58:18,150
So you get scooped quite often. Um, I'm old enough not to worry so much, but of course that does matter to the students postdocs.

493
00:58:18,360 --> 00:58:23,310
And you've got a pretty big team. Yeah, I suppose we are about 12 people at the moment.

494
00:58:23,620 --> 00:58:29,340
Well, it's not. It's not. It's not. It's not massive. Then what you'll, what you'll see on many of the papers is highly collaborative.

495
00:58:29,820 --> 00:58:34,980
Oh yes. No, I project pictures on the website. Maybe this I haven't gone to the recent.

496
00:58:35,580 --> 00:58:37,450
Um, it's quite a influx office.

497
00:58:37,600 --> 00:58:47,380
The average group member I should, I should check this properly but you know three years is a normal sort of peer of somebody being lab and,

498
00:58:47,420 --> 00:58:50,700
and quite often a bit less, um, occasionally a little bit longer.

499
00:58:51,240 --> 00:58:58,230
Um, so they turnover quite rapidly and getting grants and not getting grants and all that sort of stuff affects the dynamics.

500
00:58:58,500 --> 00:59:04,860
But yes, the authors of the papers are enormous. I mean, that's, that's been an eye opener, something I'm a little bit well, I don't know.

501
00:59:04,860 --> 00:59:14,070
It's a cultural difference, I think. Um, so in a, in a, in a regular non-clinical science paper, you will,

502
00:59:14,550 --> 00:59:22,170
you'll normally have one or two people who've done most of the hands on experimental stuff and they'll be at the front in the biological sciences.

503
00:59:22,170 --> 00:59:29,330
They'll be the front end of the author list. And you'll generally have one person who is the supervisor of them, and you might get an extra person.

504
00:59:29,370 --> 00:59:33,420
That was me. And that would be a normal size of of author list.

505
00:59:35,400 --> 00:59:43,140
In these multicenter studies, of course, you have for every cent you've got at least one principal investigator.

506
00:59:44,130 --> 00:59:47,850
So the back end of this string is, is really quite large.

507
00:59:48,750 --> 00:59:52,200
And then you've got a lot of people doing the individual experiments.

508
00:59:52,200 --> 00:59:55,529
If you imagine one of our neutralisation assays will very often take three

509
00:59:55,530 --> 00:59:59,520
or four people hands on just to do that neutralisation batch of experiments.

510
00:59:59,700 --> 01:00:05,540
So that's a lot of people to put in there when these are collaborative trial, uh,

511
01:00:05,550 --> 01:00:16,200
collaborative pieces of work with clinicians and, and also there's a vast number of players, all of whom.

512
01:00:19,660 --> 01:00:21,520
Tend to become horses one way or another.

513
01:00:21,970 --> 01:00:30,130
But it becomes, I think, one of our papers, like 60 or 70 or something like that, many of whom I don't even know or actually what they did.

514
01:00:31,700 --> 01:00:38,169
Um, and I think there is a bit of a tendency to have people on there just because they held a tube once or something like that.

515
01:00:38,170 --> 01:00:47,260
But then they're somewhere hidden in the middle. Um, so it is, but it's, it's, it's a very, very different sort of social dynamic.

516
01:00:47,620 --> 01:00:52,899
Um, not one I'm entirely comfortable with because it, on the one hand you say, well, just,

517
01:00:52,900 --> 01:01:01,420
just add blogs on because I'm sure, I'm sure, I'm sure he was, it was useful, but from a scientific integrity point of view.

518
01:01:03,010 --> 01:01:08,320
So I just follow the tone. I think it's important if your name is on a paper that you can answer for the paper.

519
01:01:08,890 --> 01:01:11,890
Yeah. And you can, you can say, well, what did I do?

520
01:01:11,890 --> 01:01:18,549
And can I just, uh, vouch for the reliability of the information that I'm responsible for in the paper?

521
01:01:18,550 --> 01:01:21,360
And ideally, I can make the whole thing, whole thing in one way,

522
01:01:21,450 --> 01:01:26,200
because I was present at the times when the raw data was discussed and analysed and when I said,

523
01:01:26,200 --> 01:01:31,400
Well, that's becomes impossible with these large teams. And so you can't really hold everybody you can.

524
01:01:31,420 --> 01:01:37,420
But I think people recognise that anyway. It's a small number of people at the back end are responsible for everything.

525
01:01:39,440 --> 01:01:43,370
So I mean, we're now it's August 20, 22.

526
01:01:44,270 --> 01:01:47,000
Well over two years since all this started.

527
01:01:47,360 --> 01:01:53,090
But it sounds as though you've got a number of lines of research that started because of the pandemic that is still very much going,

528
01:01:53,540 --> 01:01:54,740
you see right now.

529
01:01:55,860 --> 01:02:07,310
So, yes, in 2020 until the autumn, I suppose, I was very much in the mode of, well, I've put my work on hold, I'm doing the service work.

530
01:02:08,030 --> 01:02:13,229
Yeah. Because that's what the urgent takes priority over the important as it were.

531
01:02:13,230 --> 01:02:21,650
Yeah. Uh, I came to the realisation last year that not only were there some lines of work coming out of what

532
01:02:21,650 --> 01:02:26,330
we were doing that were actually scientifically interesting and but I would want to see through,

533
01:02:26,870 --> 01:02:30,560
but also that because of my advanced years,

534
01:02:31,730 --> 01:02:44,040
the effort involved in restarting the complex HIV latency microbial model stuff was to basically starting from scratch again with nobody,

535
01:02:44,040 --> 01:02:53,449
with any experience. There was too much involved in getting that going again for it to be realistic in the remaining chunk of my period.

536
01:02:53,450 --> 01:02:57,420
So I've kind of reconciled myself to not doing any more HIV work.

537
01:02:58,190 --> 01:03:03,110
So, um, the, the SARS-CoV-2 work carries on,

538
01:03:03,110 --> 01:03:09,410
including the very applied stuff like the emptiness and nanobodies stuff and the very basic stuff about the,

539
01:03:09,650 --> 01:03:12,980
the infection pathways and the defence by macrophages.

540
01:03:13,760 --> 01:03:21,380
And I think that's, that's all good. That's interesting. Um, and people are getting papers out of it and it's, and it's a good contribution.

541
01:03:21,770 --> 01:03:27,440
The neuroinflammation stuff is now restarted and that's back running.

542
01:03:27,440 --> 01:03:31,280
So that's relatively unchanged. Big thing that's changed.

543
01:03:31,280 --> 01:03:35,810
So my research direction has changed. Um, and I'm reconciled to that.

544
01:03:36,740 --> 01:03:45,380
The big thing that changed and I was really, really worried it wasn't in a healthy place was the research culture, the lab culture.

545
01:03:46,130 --> 01:03:52,100
And I said there's real upsides to the whole, um, ability to do things remotely.

546
01:03:52,670 --> 01:03:59,600
There are huge upsides. Communications across the globe have been much more facilitated by this.

547
01:04:01,460 --> 01:04:05,390
But a lab, at least a wet lab of sort. We are. We're not a theoretical lab.

548
01:04:07,620 --> 01:04:14,890
Does rely on accidental encounters between students, postdocs, technicians and peers on a day to day basis.

549
01:04:14,920 --> 01:04:18,360
Oh, how do you do it? What's gone wrong here? All that sort of stuff.

550
01:04:18,810 --> 01:04:22,590
And because for 18 months and more,

551
01:04:22,590 --> 01:04:27,120
we were under strict instructions only to come to the lab as briefly as possible to do the

552
01:04:27,120 --> 01:04:30,330
things that can only be done in the lab and to do as much as we could back in our homes.

553
01:04:30,870 --> 01:04:38,070
That culture really rather went away, and it was long enough to be the majority of a cycle of most of the people in the lab.

554
01:04:38,300 --> 01:04:43,620
Yeah. And so I was really, really worried when we started to ease the restrictions eased.

555
01:04:43,620 --> 01:04:48,510
The people weren't just coming back spontaneously. Then they'd find they could indeed do stuff with them.

556
01:04:48,550 --> 01:04:57,210
In fact, I've changed my pattern, so I will often work one or two days a week at home on things like my lectures or what have you,

557
01:04:59,550 --> 01:05:03,360
which I would never have thought about doing before, but never crossed my mind.

558
01:05:03,630 --> 01:05:07,620
So I can't blame the lab members for doing something similar, I suppose,

559
01:05:08,400 --> 01:05:16,770
but it has come back largely and the café is now buzzing again in the department, which is really because it was.

560
01:05:17,160 --> 01:05:22,940
That's pretty grim when it's just tumbleweed in the cafe. Just the department wasn't working then, but it is again.

561
01:05:23,040 --> 01:05:27,240
So I'm really I'm quietly optimistic, really.

562
01:05:27,270 --> 01:05:30,450
That sounds like a good balance because yes, there are certain kinds of work,

563
01:05:30,450 --> 01:05:34,200
but it actually is much easier to get done if you can totally focus at home. Absolutely.

564
01:05:34,320 --> 01:05:37,610
That's why my colleagues used to come in here to do some quiet work. Yes. Yes.

565
01:05:37,780 --> 01:05:42,509
So, yeah. Where my colleagues were at the moment. Because.

566
01:05:42,510 --> 01:05:44,220
Yes, because there's exactly.

567
01:05:44,230 --> 01:05:50,690
First for something where your work is, you know, if you're trying to get the words just right and framing arguments and something like that,

568
01:05:50,700 --> 01:05:55,019
if it's that sort of thing or you're trying to do a piece of deep analysis being

569
01:05:55,020 --> 01:05:59,280
interrupted every 10 minutes by somebody has to pass your office door isn't great,

570
01:05:59,280 --> 01:06:04,379
is it? Lose your friend. So, yeah, I agree with you.

571
01:06:04,380 --> 01:06:06,480
I think it's I think it's in a healthy place.

572
01:06:07,470 --> 01:06:11,549
And we have to think about using our labs differently than on, say, the place you're spending your whole time.

573
01:06:11,550 --> 01:06:22,630
So maybe more and more people can be members of the labs and the bench space seems to dictate hot desking, hot dog benches.

574
01:06:22,650 --> 01:06:32,160
We have we have started we because we moved lab um uh oh almost a year ago now and we decided to do it hot benching.

575
01:06:33,270 --> 01:06:41,870
Um, it sort of works. It sort of works and it's quite good because it stops the members of the lab from being messy.

576
01:06:41,880 --> 01:06:46,770
So they have to clear up each time. And that's good for safety and for all sorts of reasons.

577
01:06:49,060 --> 01:06:54,390
I can't remember if you said you still had any responsibility for undergraduate teaching, but that must have been something that.

578
01:06:54,400 --> 01:06:59,040
Oh, yes, the teaching changes. No, I had no, really.

579
01:06:59,080 --> 01:07:05,710
I've been on sabbatical this year, proper old conventional sabbatical, and I haven't been doing college teaching or,

580
01:07:06,430 --> 01:07:09,790
uh, university teaching this 12 month period just about to come to an end.

581
01:07:10,270 --> 01:07:18,010
But no, I threw out the, the peak time I was doing my full tutorial stint as well as everything else.

582
01:07:18,400 --> 01:07:23,410
Um, and, uh, yes, actually, almost in almost all respects.

583
01:07:23,410 --> 01:07:27,549
I enjoy the teaching. So because to be honest, in Oxford we don't get overburdened.

584
01:07:27,550 --> 01:07:32,770
And I know people do complain a lot, but, you know, it's not the same as 40 hour teaching week in some institutions.

585
01:07:32,890 --> 01:07:36,790
But you were doing it on zero teams. I was doing it on, on, on teams.

586
01:07:37,010 --> 01:07:48,160
Um, there was an interesting so this interest me at least one of my students come in, I think it was in his first year, uh, before the pandemic.

587
01:07:49,630 --> 01:07:53,920
This is in their first Michaelmas term in 2019.

588
01:07:54,620 --> 01:07:57,910
Uh, got mumps and so had to go home.

589
01:07:58,540 --> 01:08:09,580
So teams was available. And so we started doing tutorials with teams so that this student could be part of the tutorial group.

590
01:08:09,970 --> 01:08:12,010
And we just kept actually the things you can do in,

591
01:08:12,610 --> 01:08:18,729
in the team's environment that are hard to do in the physical tutorial surprised me once, once, once you know each other.

592
01:08:18,730 --> 01:08:26,080
I think that's that's the key thing. So we were in a good position to carry on doing our teachers, our teams, and that actually worked extremely well.

593
01:08:26,440 --> 01:08:36,540
Um, and lectures. It liberated the lectures. Uh, so our final lectures I run a, um, a theme on them emerging infections.

594
01:08:36,850 --> 01:08:46,540
Um, and I was able to, because we weren't gonna have any physical lectures then it liberates you from the 50 minute timetable of, of a didactic slot.

595
01:08:46,540 --> 01:08:51,430
You know, you can break it up into whatever length of piece is needed for that piece of intellectual stuff.

596
01:08:51,700 --> 01:08:57,370
And you can do more interactive things and you can get people willing to give you 7 minutes

597
01:08:57,370 --> 01:09:02,950
of interview online and record it from from Sydney or from Beijing or what have you.

598
01:09:03,550 --> 01:09:11,200
So it gave us a lot more, a lot better set of experiences for the students, frankly.

599
01:09:11,710 --> 01:09:21,610
Um, and I've yet to meet a student who says, given the choice, they would rather have only in-person rather than only pre-recorded lectures.

600
01:09:21,850 --> 01:09:25,360
They quite liked having the opportunity both. But so they were they were pre-recorded.

601
01:09:25,360 --> 01:09:30,249
We weren't doing them live over. No, the exactly the lectures were pre-recorded.

602
01:09:30,250 --> 01:09:39,400
We were doing some live seminar things where the students got lots of questions, but those carried on in the chat box afterwards anyway.

603
01:09:40,230 --> 01:09:46,030
So and the feedback and that was in the first year for doing that was tremendous.

604
01:09:46,030 --> 01:09:51,190
They really loved it. So and partly because they'd all had to stay at home.

605
01:09:51,790 --> 01:10:00,189
So but they were still able to engage with with with the course in an exciting for these mostly medical students most

606
01:10:00,190 --> 01:10:06,909
of mine in medical but being the biomedical sciences students also take these options as a smaller number of those.

607
01:10:06,910 --> 01:10:17,050
But yeah, um, so I'm hoping we aren't going to just revert too fast to having to do things in the conventional way because I think there's a lot,

608
01:10:17,950 --> 01:10:21,370
there's a lot to be said for using some of these modern technologies.

609
01:10:21,580 --> 01:10:30,400
Now it sounds as if you were using it in a fairly inventive way. So is there a movement, do you think, in the university to develop that?

610
01:10:30,850 --> 01:10:38,200
I don't know that what I hear most is the urge to return to good old fashioned normal.

611
01:10:38,560 --> 01:10:43,330
And I you know what? You've been exposed to the educational research as much as I have.

612
01:10:43,330 --> 01:10:47,920
There's you know, there's limited educational value to the purely didactic sessions, isn't there.

613
01:10:47,950 --> 01:10:56,080
You know, and um, and the equivalent on examining, um, which is that one bit of the whole thing I don't like at all,

614
01:10:56,620 --> 01:11:05,620
um, that we, the glimmer of good things was we obviously people weren't able to come to exam schools to do the exams.

615
01:11:05,950 --> 01:11:09,760
So we were allowing people to send in TypeScript.

616
01:11:11,070 --> 01:11:17,050
There was a degree of sort of proctoring to make sure they weren't cheating, but that's what happened.

617
01:11:17,590 --> 01:11:23,440
The back end sort of administrate the the technical side of the administration didn't work brilliantly,

618
01:11:23,440 --> 01:11:27,850
but at least we weren't having to decipher people's awful handwriting, which is just grim.

619
01:11:28,930 --> 01:11:32,919
I've never saw handwriting three, as is a life skill anybody needs to acquire anyway.

620
01:11:32,920 --> 01:11:38,050
So why we forced them to do it? I don't know. Certainly reading it is not a skill I need to acquire.

621
01:11:40,120 --> 01:11:47,500
And tragically they're going back to the you know, I kept all of the clunky bits of.

622
01:11:48,590 --> 01:11:55,430
Computer administration of the exam process. The bits that didn't work very well, but made them revert to handwritten scripts.

623
01:11:58,190 --> 01:12:05,870
Anyway. It's all the wrong bits of conservatism, I'm afraid. Um, but we are hanging on too much.

624
01:12:06,210 --> 01:12:08,510
No, I hope not. I do hope not.

625
01:12:08,930 --> 01:12:15,590
There's always some excuse why it's too difficult to prevent cheating or having the right number of keyboards or something.

626
01:12:19,070 --> 01:12:22,910
So I'm just turning to how the whole thing affected you personally.

627
01:12:23,840 --> 01:12:27,260
I mean, obviously, you had the dispensation to come into the lab, if you like.

628
01:12:27,290 --> 01:12:35,180
Yes. Yes. It was slightly odd when everybody else was saying, gosh, isn't it annoying to be at home all the time of all of us?

629
01:12:35,480 --> 01:12:40,520
I was actually going to the lab all the time, uh, you know, really quite long hours.

630
01:12:41,120 --> 01:12:45,770
So that was a bit odd. Hmm. Yeah. So that was my next question. What kind of did it change that?

631
01:12:45,830 --> 01:12:50,000
The obviously I mean, you are obviously somebody who works very hard anyway, but did it change the hours that you worked?

632
01:12:50,450 --> 01:12:56,960
I don't know if I do. I don't see a virtue in working hard, not when most people think that working smart is a good thing.

633
01:12:57,660 --> 01:13:02,140
Um, I was working long, very long hours and did get very tired.

634
01:13:02,150 --> 01:13:11,380
And Becky, for example, as I'm sure you know, yeah, people that had to do that and home school kids had an extra, you know, very, very challenging.

635
01:13:11,390 --> 01:13:21,410
And given my advanced years, it did affect my health quite badly physically for a while, which is now all resolved.

636
01:13:22,310 --> 01:13:33,200
But no, um, yeah. That level of high stress, intense work for long periods is something that's harder to do when you're in the sixties, to be honest.

637
01:13:35,390 --> 01:13:42,860
So I learnt my limits. And did you feel personally threatened by the possibility of infection before the vaccination came along?

638
01:13:43,690 --> 01:13:47,790
Um. Interesting.

639
01:13:47,910 --> 01:13:51,780
I mean, that's. Yeah. Interestingly, in the P three containment lab.

640
01:13:52,320 --> 01:13:55,110
Not at all. Because I know how to handle the things in there. Yeah.

641
01:13:57,240 --> 01:14:07,530
But, yes, outside the lab, I suppose I was more conscious than the average member of the public about the chance of infection.

642
01:14:08,310 --> 01:14:13,650
So when I was insisting on wearing a mask going into a shop, people would look at me like I was mad.

643
01:14:14,640 --> 01:14:22,080
In the early days. Now people aren't. So the best line to do that, that people are now a little bit odd in wanting to cross the street,

644
01:14:22,080 --> 01:14:27,690
even if on a country road they are walking when the chances of catching something terrifically low.

645
01:14:28,350 --> 01:14:33,360
But no, I don't think in my in my day job, I was exposed to any any high, higher risk.

646
01:14:33,690 --> 01:14:39,360
The slight the only frustrating thing was that at one point, we we were in a we were put into an odd position.

647
01:14:40,350 --> 01:14:41,790
I still understand this to this day.

648
01:14:43,380 --> 01:14:53,100
There wasn't draft edict coming around the university saying thou shalt not work on the variants of concern that have emerged.

649
01:14:53,100 --> 01:14:56,250
This is when alpha and beta were just coming along.

650
01:14:56,940 --> 01:15:02,159
Unless thou hast been vaccinated. And I said, Well,

651
01:15:02,160 --> 01:15:07,379
we are working on them and the vaccine is not available to us because scientific

652
01:15:07,380 --> 01:15:11,640
work is did not count as a category of person that got the vaccine properly,

653
01:15:11,640 --> 01:15:16,050
correctly. But, you know, don't do this, please.

654
01:15:16,080 --> 01:15:18,870
This is rather important that we managed to establish.

655
01:15:18,870 --> 01:15:23,910
Whether the current vaccines are giving protection against these new variants is one of the things that we did.

656
01:15:26,730 --> 01:15:33,420
So that went on for a surprisingly long time, the sort of threats to close this down that went away.

657
01:15:33,720 --> 01:15:38,280
I still don't know this day what really motivated all that. There was some being some its bonnet.

658
01:15:39,270 --> 01:15:42,929
Uh, but no, I didn't. And I have.

659
01:15:42,930 --> 01:15:46,740
I haven't caught the virus after after my two doses of vaccine.

660
01:15:47,160 --> 01:15:50,280
I got the the the April wave, like many people did.

661
01:15:50,620 --> 01:15:54,390
Um, April 21. April this year.

662
01:15:54,570 --> 01:15:57,980
Oh, yes, yes, yes. Uh, back to probably.

663
01:15:57,990 --> 01:16:02,160
Yes. Um, uh, and it wasn't very pleasant, actually.

664
01:16:02,170 --> 01:16:09,149
11 days of antigen positivity and, and in bed for a two or three days feeling really quite sorry for myself.

665
01:16:09,150 --> 01:16:18,450
But. But no actual snow, no severe temp, no temperature, and no oxygen depression.

666
01:16:18,450 --> 01:16:26,279
So nothing. Nothing. Nothing to complain about, frankly, uh, this goes to show this thing is quite, quite good.

667
01:16:26,280 --> 01:16:30,210
It'll be infecting you even after you think you've had immunity.

668
01:16:30,430 --> 01:16:38,130
Mm. And were you involved in the COVID safety regime for the department?

669
01:16:38,440 --> 01:16:42,150
We did. We know that they did the university.

670
01:16:42,450 --> 01:16:44,880
Well, there was in the eighties in the university.

671
01:16:45,280 --> 01:16:50,720
No, we had a we had a I think it's a silver group with one of those precious metal groups in the department.

672
01:16:51,330 --> 01:16:57,420
But quite rightly that didn't involve me or anybody that was had a vested interest in it.

673
01:16:57,440 --> 01:17:04,169
Yeah. So that involved senior members administration and and academics not involved in

674
01:17:04,170 --> 01:17:07,860
that and including microbiologist not involved in this House committee stuff.

675
01:17:08,460 --> 01:17:17,190
But then that was, that'll work pretty well. Um, they were possibly more cautious than I would have been about the general return to work thing.

676
01:17:18,000 --> 01:17:20,040
They wanted to be on the safe side,

677
01:17:20,040 --> 01:17:29,759
which I think the downsides of having a scientific environment becomes less vibrant is it was worth weighing or any,

678
01:17:29,760 --> 01:17:34,700
but it did quite a good job and I wouldn't have wanted to be in that.

679
01:17:34,860 --> 01:17:39,860
Yes. And do you think I mean,

680
01:17:39,860 --> 01:17:51,980
a lot of people found the the regulations and the conditions that they had to live under quite hard in various psychological as well as physical ways.

681
01:17:52,490 --> 01:17:55,969
Do you think the fact that you were able to work on something that was going to

682
01:17:55,970 --> 01:18:00,080
contribute to solving the problem might help to support your own work smoothly.

683
01:18:00,290 --> 01:18:05,540
Yeah. I have overworking, I think. Yeah, I think I would find it extremely hard.

684
01:18:07,250 --> 01:18:14,329
Uh, they're extremely hard not to have been able to go to work, because there's only so much I can do.

685
01:18:14,330 --> 01:18:22,580
Theoretically, I'm not a theoretician. Um, so I am very glad that I was able to do something practical.

686
01:18:22,580 --> 01:18:29,600
And I think that might, in the back of my mind, swayed because it was a matter of choices whether I volunteered to do this, this thing or not.

687
01:18:29,600 --> 01:18:33,140
And I think that was probably at the back of my mind. I don't want to be twiddling my thumbs.

688
01:18:34,010 --> 01:18:40,069
I can do this. I should do this. I will do this sort of thing. Um, so, yeah, exactly.

689
01:18:40,070 --> 01:18:43,639
Um, enforced idleness would not have suited me at all.

690
01:18:43,640 --> 01:18:48,020
I don't think voluntary idleness now is looking more and more appealing.

691
01:18:48,060 --> 01:18:51,290
But it isn't, it's not going to come any time soon.

692
01:18:51,680 --> 01:19:00,770
Mhm. And have you been involved in any national bodies that have had to do with policy in any.

693
01:19:01,470 --> 01:19:09,950
I've been involved in some international bodies but long with lots and lots and lots of other people.

694
01:19:10,190 --> 01:19:15,499
But no, not on the not on those ones that you hear about that are advising governments on which vaccines to deploy or.

695
01:19:15,500 --> 01:19:25,190
No, none of those. Uh, I'm not sure that I well, anybody who knows about the viruses could be useful on those things,

696
01:19:25,190 --> 01:19:30,110
but I think the people are more use for the public health physician and so on, frankly.

697
01:19:30,110 --> 01:19:37,040
Um, uh, yes, in advising on public policy in these areas, not something I will have to do.

698
01:19:37,820 --> 01:19:44,790
But pandemic preparedness generally presumably involves making decisions about what kind of research needs supporting.

699
01:19:44,810 --> 01:19:53,629
Yes, yes, absolutely. So I, I don't have any positions of responsibility there, but I do have very close connections with, uh, with the people who do.

700
01:19:53,630 --> 01:19:58,910
And so we discuss these sorts of things like quite happy with that having had six years of this previous done.

701
01:19:58,910 --> 01:20:03,560
So I'm not, not, not looking for extra explicit responsibilities again.

702
01:20:05,270 --> 01:20:08,719
Okay. I think, I think we're pretty much done. Yeah. Um, so my,

703
01:20:08,720 --> 01:20:16,160
my final question is whether the experience of working on these SARS-CoV-2 problems has changed your attitude or your

704
01:20:16,160 --> 01:20:22,240
approach to your work and what it hasn't given you insight into things that you might want to change in the future?

705
01:20:22,250 --> 01:20:25,430
Gosh. Well, I think so. I think we've we touched on a few of these, haven't we?

706
01:20:25,430 --> 01:20:29,120
So I think patterns of work can change a bit.

707
01:20:29,810 --> 01:20:34,160
There are things about the old pattern of work that are worth getting back a little bit.

708
01:20:34,430 --> 01:20:37,729
Patterns of teaching can change and should change.

709
01:20:37,730 --> 01:20:42,270
Patterns of examining should change in much, much more, much, much more.

710
01:20:42,320 --> 01:20:45,320
Right. I'm a bit of a radical about examining. Um.

711
01:20:47,890 --> 01:20:51,040
Yeah. Life generally. Yeah. So. Yeah.

712
01:20:51,040 --> 01:20:54,520
So so wasn't well it.

713
01:20:57,310 --> 01:21:02,920
I don't know if you around Oxford at the time in that first lockdown how quiet the place was to

714
01:21:02,920 --> 01:21:09,440
work at walking direct is when the only person in the middle of a working day in the square.

715
01:21:10,330 --> 01:21:16,510
Absolute silence. And at first I thought, Oh, isn't this charming?

716
01:21:17,830 --> 01:21:24,040
And I thought, No, it's actually a bit post-apocalyptic. And then I sort of have that add.

717
01:21:24,040 --> 01:21:29,139
It had the reverse thing earlier on this year, especially around Easter,

718
01:21:29,140 --> 01:21:34,900
where I was walking Interactive Square and you couldn't get through it because of all the tourists and everything else.

719
01:21:34,900 --> 01:21:42,130
So. Which one? I don't know. It's made me even less inclined to go travelling than I.

720
01:21:42,730 --> 01:21:51,190
Otherwise I'm not a great traveller. I don't. I'm not keen on globetrotting and so on, and I've used as an excuse not to do that.

721
01:21:51,820 --> 01:21:55,270
And plus the environmental excuse not to do that. Um.

722
01:21:58,110 --> 01:22:03,480
But I yes, I think yes, I think that's that's just maybe which is things I probably would have done that way anyway.

723
01:22:06,330 --> 01:22:09,390
This is an awkward thing to tackle in the end, but I forgot to ask it earlier.

724
01:22:11,010 --> 01:22:14,100
But was it easy to get funding for the work that you've done?

725
01:22:15,690 --> 01:22:21,120
There was. Well, we should give a plug. I don't know if you use your tokens them elsewhere,

726
01:22:21,120 --> 01:22:34,080
but the Development Office and the Medical Sciences Development Team did an excellent job of rattling the cans and got a strategic fund together.

727
01:22:34,450 --> 01:22:42,450
Attitude. Patrick Grant It's about that whole area and that was administered in a, in a, in a very imaginative way.

728
01:22:42,480 --> 01:22:49,560
Um, um, difficult job to administer that, but they did well, so, so for setting up the,

729
01:22:50,060 --> 01:22:54,360
the service sort of function that we did and for doing one particular piece of

730
01:22:54,360 --> 01:22:59,280
work where applying through the conventional routes would have been far too slow.

731
01:23:00,150 --> 01:23:07,860
Um, that's enabled us to do what we needed to do. Um, um, and I think quite a lot of groups around Oxford found that as well.

732
01:23:07,860 --> 01:23:21,659
So that's been brilliant. Um, we've continued in, uh, in a certain respect to use, to use, to work with philanthropists,

733
01:23:21,660 --> 01:23:28,110
donors to fund research since, um, in a way that's wasn't normal before, actually.

734
01:23:28,710 --> 01:23:32,730
Um, and I think maybe that sort of culture has changed a little bit.

735
01:23:33,720 --> 01:23:39,850
Um, it's different, but, um, yeah, so it's, it's another way of getting, uh,

736
01:23:40,110 --> 01:23:45,719
the science that needs to be done, supported and engaging a wider range of people in science.

737
01:23:45,720 --> 01:23:49,800
So that's been good as well. Good.

738
01:23:52,310 --> 01:23:52,610
Good.