So could you just start by saying your name and your title and affiliation?
I'm Alan Townsend, and I'm Professor.
My official title is Professor of Molecular Immunology, although I was an honorary consultant physician here too for a long time.
Um, and, uh, I work in the Weatherall Institute.
I've been here since 1989, came to Oxford in 1983, literally in the Department of Surgery with Peter Morris.
Yeah. So with that, my next question is. Without telling me your entire life story.
Yeah. Could you just starting from when you first got interested in medicine?
Yes. The two main stages of your career up till now.
Yes. So I was at St Mary's Hospital Medical School and, uh, I had had very good teaching at my high school and in biology and chemistry and so on.
I knew I wanted to be a doctor from the age of about 17, I suppose. Um, and at Mary's I was really tremendously inspired by Professor Stan appeared.
He was a brilliant general physician.
He'd got an FRC himself, um, for his work in the isolation of West and if I remember rightly, from, from the spleen and working with Sir Henry Dale.
But he was an inspired teacher, a brilliant clinician.
Patients adored him and a great teacher and demonstration at the bedside.
And so I wanted to be like him, basically.
So I, I, I loved clinical medicine, but I had become aware that science, you know, the science of medicine was extremely interesting.
And in fact, there that little book taught by NAS Introduction to the Study of Experimental Medicine.
So I try and get everybody to read. He comes to the lab. I got introduced to that not by Stan, actually, but by the professor of surgery.
He was a very interesting character called Hugh Dudley, and I was editor of the Gazette and I asked him, amongst others, to write book reviews.
So I wanted him to write a book review and a Little Book on Surgery by Zachary Cope.
That was a great memories person in In Doggerel Verse.
And Mr. Dudley did not have a tremendous sense of humour and he thought, this is a load of rubbish and he wouldn't dream of doing anything.
So I sort of backed out of his office, but then he said, I will write you an essay on Claude Banana.
So I thought, I wonder if that'll happen.
Anyway, he wrote this fascinating essay about this book and about Claude Banal basically was pretty popular in popular.
I mean, it was a biological it's popular in approach to science.
And then and it's a fascinating account of his own research as well.
And I was fascinated and I went to look for the book, eventually found it in the library,
and later I met him and I thanked him for his article and he said,
yes, took a little bit of effort because I couldn't find the original and I had to do it all from memory.
And he'd quoted extensively, of course, he's that sort of chapter tremendous memory.
So that book really inspired me.
And I, you know, I talked about it a lot to Stan when we had time and stands.
Ward rounds were extraordinary because we were reasonably busy, the London Teaching Hospital,
but on the ward round we would discuss each patient with the patient, you know, fully involved, fascinated by the dicky bow.
And we'd go through the management of the patient, given the information we had.
But then he'd go on to what research was relevant and it just, you know,
we'd get it seemed to me we'd get to the end of human knowledge and then we'd move onto the next patient.
And so Waldron's did take a bit of time, but he was inspiring.
So I wanted to do research and I went on after a bit of thinking,
I ended up deciding to go to the National Institute for Medical Research to work with you to ask Anais and John Scahill on flu,
because by that stage I'd got my ideas sorted out and I realised that immunology was a very much under-researched thing,
that there were massive new tools coming in pre molecular biology, but there was the cell sorter,
there was cloning, there was cloning of cells and monoclonal antibodies had arrived.
And it struck me that these were very powerful tools to investigate horrible
diseases like M.S. and and as viruses seem to be likely to be involved in mice,
and the MHC was beginning to be understood, not understood, but at least was being studied.
An MHC restriction had just been discovered. That's how T cells need two components to recognise an infected cell, the self and the virus.
And this could be studied with flu better than any other virus because Mel Hill
ran the W.H.O. surveillance of flu had done from right from the beginning.
And John Scahill ran that. And they had every flu virus that had ever been isolated from humans in their freezer.
So you had all these fantastic tools and to extraordinary people.
So John Cahill, brilliant virologist and structural in a person as well,
and an eater who was a really top immunologist and I was supervised by the two of them.
And before we go any further, I think we should just do a kind of immunology.
One, two, one, one, two, one. Yes. You don't know anything about the.
Yes. Okay. So well, I lo I'm called an immunologist.
I don't really regard myself as an immunologist. I see myself a little bit as an amateur immunologist.
But, you know, I'm a generalist really, and interested in the biochemistry.
But immunology is obviously the way the body defends itself against infections, against foreign invaders.
And in my view, I think, you know, we evolve our immune systems in vertebrates have evolved to deal mainly with infections.
I mean, some people think that the cancer is involved for a variety of reasons.
I think that's very unlikely. But, um, but so we're being bombarded.
With viruses and bacteria all the time, and yet we don't die from it most of the time.
And that's because our immune system is able to protect us. And the vertebrate immune system is particularly interesting because it's adaptive.
So it's not just general mechanisms which apply, you know, a set of general mechanisms which apply to everything.
It actually adapts its response to suit the bug that's coming in.
So with, you know, COVID, just like any other virus, you make T cells and antibodies, t cells of the white blood cells and develop in the thymus.
That's what they call T for thymus and the antibodies which are produced by B cells and Basler Fabricius I won't go into all that,
but the original discovery of them was in the birds in this thing called the Bursa and B cells,
and these combinations,
the antibodies are soluble proteins that are in your blood and in your extracellular fluid surrounding all the cells in your body that can get there.
And t cells are these cells which clamber through out of your blood and come through the tissues looking for trouble, as it were.
And if a t cell finds an infected so of your body, it'll kill it, destroy it,
and that will get rid of the virus and or prevent the cell making more viruses and the antibodies do lots of different things.
But probably the main thing they do, or the thing we understand best is they bind to the virus and prevent it getting into your cells.
There are lots of other things they can do, but to me that's the most easily comprehensible.
That's very helpful. Thank you. Yeah. So anyway, John and Ito have been very knowledgeable about all of this.
And the big question at the time was, what do T cells see?
What do they recognise? Because it was clear they recognised something specific.
So they recognised in a virus infected cell but they didn't recognise that influenza B virus infected cell.
What was it about the cell, the infected cells they recognised and we knew by that stage from, from Dr. and Zinckernagel.
These are two people who won the Nobel Prize in 95 I think it was.
But the key observations in 1974 were that the that the bits of you that vary between individuals that make tissue transplantation so difficult.
The real role of those proteins is not to thwart the transplant surgeon, but to help you recognise infected cells.
And so it was known that the T cells needed a component that's called the major histocompatibility,
complex, horrible words, but a bit of you that varies between individuals and something from the virus.
But how these got together, nobody knew.
And it was very it seemed to me very important because there were lots of horrible diseases like M.S, for instance,
or Ankylosing Spondylitis, etc., where those diseases occur much more frequently in people with particular tissue types.
And so if we really understood how T cells worked, maybe we could have insight into all those diseases.
So and I thought, right, that's it. That's a really, you know, that's what I want to do.
So and those diseases are appeared to be an overreaction.
And to be honest, is that wrong? Well, to be honest, I mean,
there is some evidence that recently there's been a lot of excitement because
there's a statistical association between Epstein-Barr virus infection and mice.
But the causal relationship,
I'm still it's very difficult to understand because the vast majority of people who get Epstein-Barr virus don't get them.
And so and there are similar things going on with ankylosing spondylitis,
but one of the things that's always troubled me is that we know very well how t cells work now, but we still don't understand these diseases.
Not really. So they are attacking the cells?
They are, yes. And that probably t cells involved. Certainly they're involved in mice with at closing.
Still not absolutely clear to me anyway, but I'm a bit, you know, a bit of a donkey with these things because,
you know, things come in and out of fashion, views come in and out of fashion.
But the evidence isn't always 100% clear anyway.
So but that's what I want to do. And at the time we had these different viruses, but we didn't have molecular biology,
so we couldn't take one gene at a time and express them in cells.
It's the obvious thing to do. Couldn't do it, but there were techniques for distinguishing the the eight RNA segments which are in a flu virus.
They vary between viruses and some nice work from the states and at the Mount Sinai had been done to show that you could run these you could take pure
virus and run it out on a Polyacrylamide gel just separates the RNA segments and they move slightly differently depending on where they come from.
So if you have a virus that has two parents and you cross the parents and you get lots of little viruses, as it were, you can.
Tell which gene came from which parent. So that gave us a pretty strong tool and basically took a very long time and a series of lucky breaks.
So then there was this big chemical question how does a protein that's in the nucleus get recognised at the cell surface?
And initially I had a bit of trouble with that because some very senior people said That can't be right, you know.
But and this is where I think technology is so important that if you really know your technology and if it's as solid as a rock,
they can repeat the experiment. And it's not difficult.
You don't need special skills. And so eventually the the the big boss, Rolf Singh and Al Gore basically repeated the experiment and or did repeat it.
So I sent him all the kit to do it. And then he said, Yeah, I believe you, you know.
At the time he was a bit doubtful, which is fair enough and fair enough.
So then. And as a student, you know, being doubted by such a senior person was a very testing experience.
But it didn't last long. And once it was over, he was very supportive and always very kind.
So. And so the T cell couldn't possibly recognise something that was in the nucleus because that's kind of buried behind.
It's buried behind the membrane. So how did it. Now, of course, these things are always more complicated.
So there were people who claimed that the nuclear protein was detectable at the cell surface.
So what was the problem? But biochemically, that didn't make sense because.
It was known by that time that a protein which gets to the cell surface and is inserted
in the membrane of the cell surface has certain signals that direct it there.
So particularly the thing called the signal sequence at the front, which pushes it into a part of the so called endoplasmic reticulum,
which is topographically external, and then it moves up to the surface.
Now cells without that shouldn't be at the cell surface, you know, unless there's some other mechanism for proteins without that.
I think you said cells without that. But you mean proteins? Proteins without that sort of.
Yes, proteins without that signal sequence. So.
But by that stage, molecular biology had arrived and we had cDNA DNA copies and we could express these in the expression vector.
So you could put genes one at a time into cells. And we did that.
And the nuclear protein was all it was required, didn't require anything else.
So had these cells that had just expressed nuclear protein, you could stain it in the nucleus, couldn't stand it on the cell surface.
And they were recognised very, very strongly by the T cells.
And I tried to publish that and I got a barrage of abuse from the referee saying this is impossible.
I said, Well, that's the data, it's possible. And then, you know, so but then, you know,
it had lots more controls and we had t cells that recognise the nuclear produced from from different viruses and so forth.
And that eventually was published in a set of papers.
And I then moved on to just asking very simple question what if there isn't a signal sequence that we can see,
maybe there's some hidden signal sequence or something. So a friend of mine was working on the movement of that protein into the nucleus,
and he had chopped up the gene and expressed different bits and showed that there was a signal which took it into the nucleus.
So I said, Well, could I use the bits? And we'll just see what happens. The recognition surface.
And the other thing that was very obvious when the biochemistry, these bits which don't fold fully,
were degraded very rapidly in the cell and in some cases I couldn't detect them at all.
That also gave a big problem to the referees, as if you can't detect the protein.
Where is it?
But it said it was clear they were being degraded rapidly in the cytosol, in the cytoplasm and something that's been recognised at the surface.
And by that stage it was known that so-called class two restricted cells,
cells that recognise proteins that come into a cell from outside of degraded in vesicle.
So they remain topically, topographically external and they bind into a different MHC molecule and those are recognised by T cell.
So they were all sharing the same V genes that the gene pool which goes to make up the receptors are all come from the same pool.
So they must be recognising a peptide. It's just it's coming from inside.
And that took 14 years basically to go through all the bits and pieces and lots of other people, of course joined in.
But it turns out there is a special mechanism in the cell.
Proteins are degraded that transported by a different transporter into the endoplasmic reticulum where they bind to the MHC molecule that goes up.
That complex is then recognised by the T cell receptor. And so there are lots of nuances to that.
Many, many different people have contributed to that. That all arose from my in a Ph.D. and that was all very interesting.
But at the end of that, really, once we got to that stage,
I didn't feel particularly qualified to go into the minutia of the biochemistry or the minutia of the structures.
You know, the lots of people doing structures of MHC molecules with different peptides or T cell receptors and so on.
And I really wanted to go back and practice medicine. I hadn't done it for a long time, so I went back.
I kept things going in the lab of various projects, but in 1994 I went back and retrained myself.
I did four years of retraining, but two years as a chair.
And then I was a registrar and I worked with as many consultant as I could here.
They're all very good here. So you came to what I was in? Yeah, I came, doctor, in 1983, right?
To finish my day filled with Andrew. Michael to do to try and apply it to humans, which we did.
And then and so I then just went back to being a general, basically a general physician,
and I decided to work with the geriatricians because they are the best general physicians.
And how James and Simon Winnow were absolutely superb general physicians.
So I, I did my registrar work with them for two years and then they invited me to join them as a consultant on their firm.
So I did that for the next six years very happily, and I was doing basically half time.
So I it ended up being more than half time because I was doing outpatient clinics when I wasn't on the beds, but I was very busy.
I was keeping the lab ticking, very happy to the lab was here as well by then.
Yeah. So yeah but the head of the MRC was being a bit he said he wasn't being critical and he
said he felt it was a wonderful thing that I was going back and practising medicine again,
but it didn't come across like that and I'm like, you know, I had a program grant and but you know,
it was probably a bit doubtful about whether that would get renewed.
And, and because we were beginning to do a bit of work on cancer,
dying of colon cancer because it looked like colon cancer probably spewed out
aberrant proteins that might get into the system and some things like that.
But it's a bit before it's time to be honest. And again, it didn't it I mean, we did some work on it, but and then I then got cancer myself.
So I was very ill for about a year and luckily it was cured.
But then I thought, right now I'm going to do so.
I just decided to Roma sleeves up get back into the lab and I European working director
would come in which I hated because it completely changed our way of working where,
you know, junior staff for sixes and sevens they had to have rotas which is still the same now,
which all over the place they don't really have a firm structure.
We worked with one firm, you know, I as junior doctor we'd you'd do six months with one firm more than one year.
And I set my case, I, I did a year or two with them.
And you really get to know your bosses, you know their strengths, occasional, very occasional weaknesses.
And then you get to know everybody. And it's it's a very supportive environment when you're dashing,
putting out fires for one firm in another because you're only allowed to work 40 hours.
So you're never you know, I think psychologically that's far more stressful and and less of an educational experience.
Actually, you may not be so tired, but probably stressed out anyway. My opinion.
But so at the end of that and I've been ill and I talked about it how and people I decided to get back in the lab.
So I started just working, doing things.
And we've worked on various aspects of flu and developed a live attenuated flu virus that we would hope Monday will be a vaccine.
It's very difficult to get funding, serious funding for that, and it works beautifully.
And we've applied it in lots of different circumstances. We've collaborated people all over the world.
But, uh, we haven't been able to to get it commercialised.
But I'm interested in all aspects of immunology, you know, and I work, tend to work with students.
So we had a very good student. We started when it became possible to isolate monoclonal antibodies from humans,
we began to look at the monoclonal antibody response to flu, to what is a model of antibody.
And Caesar, a Milstein and Akola in 1975 fused a B-cell in a normal lymphocyte with a malignant B cell.
And this sort of experiment been done a lot by other people.
But it always turned out that the normal genes seemed to suppress the tumour genes and not much happened in this case.
They got the growth properties of the tumour, so it grew in tissue culture and it carried on producing antibodies from the original B-cell.
And because these grow very well, they'll grow a single clone.
So you end up with an absolutely pure single antibody.
And there's a classic paper that they wrote in 1975 in which in typical beautiful understatement, there's one sentence at the bottom which says,
We understand this may have commercial implications or something of that kind or, you know, may have many applications.
And Margaret Thatcher got very cross with them because they didn't patent it all.
And a lot of patents then went to the States and there was a huge hoo ha about it
and lots of people made lots of money which really should have been done in Britain.
But anyway, but that's always been, I think one of the traditions that I actually secretly greatly admire is that
we talk to people about stuff and that's why things interesting things happen.
And if we didn't talk to people, they wouldn't be interesting things. And I think the university here at the moment has lost its way a bit on this.
We're just obsessed with patenting everything and spin offs and all the rest of it.
And personally I think it's danger in that anyway to carry on with the monitor.
And so we're very interested in looking at the monoclonal response to flu because you might, you know, begin to dissect interesting things.
And one of my students actually, he wasn't my student, but he worked with us quite a lot and collaborating with us went back to Taiwan,
Arthur Fung and he's now a consultant in childhood infectious diseases there.
But he carried on with becoming very good at isolating monoclonal antibody against a variety of different infections.
And so we've been working with him on COVID because he's done a lot of isolations.
You don't get that.
So, so, so one of the things it's been a great pleasure in my career is the collaborations because I like working with a small group I've never been.
I tried to expand at one point and I just didn't. I'd much rather work with a small group of well-integrated people and then collaborate.
And we collaborate very widely all over the world with various groups who I've known for a long time, you know, and with students.
And it's it's very pleasurable, you know, and nine times out of ten, it works really well.
And you have a very open you can have very open discussion about things.
And so that's been that's been great fun and we've been very busy doing that over the last few years.
So and that was all moving forward.
And then a few years ago I met Mark Howarth, who I mentioned earlier.
Now, Mark, I have a short list of people I've met over the years who I think might be in the running for a Nobel Prize.
And he's one of them. I mean, I think he has a his work has this special quality of being fundamental in terms of fundamental insights into biology,
while also having wonderful applications that you can pick out of them.
And so I and I'm not familiar with all of his work,
but I was actually can I read a review that he'd written about an enzyme that we use a lot for putting biotin groups onto proteins and we're lazy.
And so we were buying a kit from the States and this blooming kit kept on getting impounded at Stansted.
And by the time it arrived at us, the enzyme was dead and very expensive.
So I was looking around either about thinking about making our own or anyone who was any good at making it in the university.
And then I read a review by him about in how to make it and how best to do various aspects of it.
So then I finished the review. I said, Where does he come from? He said, He's in chemistry in Oxford.
So I called him up and said, Can I come scrounge some of this stuff? He said, Sure, I'll have breakfast with him.
And then he told. About what he was now doing, which is this extraordinary piece of work he's done on understanding a particular
chemical bond in a particular protein in the streptococcus pathogens organism.
And it's a nasty bug which causes sore throats and it has all sorts of very unpleasant side effects.
So rheumatic heart disease and joint disease and all sorts of things.
And it's luckily it is sensitive to penicillin and this remains so, but it's a very unpleasant organism.
And so there's a lot of work done there. And one of the things that I'm not sure he was the first person to ever observe this,
but he picked up on is that there's a to one of the proteins which is a long chain which holds the on to your throat.
Basically it's like an anchor and has to be strong from the bugs point of view.
And is that the chain link is held together internally by a bond which is not a disulphide bond,
not disulphide bonds are bonds which form within globular proteins to hold them together in eukaryotic cells in our types of cell.
But bugs don't make those bonds, but they make now they use a peptide bond.
Now normally in our cells, peptide bonds are only sequential.
They're only between units in a long line, but not within or between chains.
And this was a between chain peptide bond, which is very unusual.
So he, being a very, very gifted biochemist, dissected it all and he found that he could take one bit of the protein out and leave the other bit.
And basically when you mix them together, the peptide bond formed and it didn't require an external energy source.
Normally, you know, you need an enzyme and a bit of ATP and double blind would be very commonly known, a bit of it.
The energy required was all encased as it were, in the sort of spring of one half.
And he realised that this was quite a nice way of sticking proteins together that you might want to stick together.
Meanwhile, immunologists had been very much aware that particular antigens, antigens that are particles like viruses,
are much more powerful at stimulating the immune system than just soluble proteins.
And of course, this has implications for vaccines. And and of course, it's kind of obvious because that's what we have to defend against.
So and various clever people in the world had been looking at manmade particles,
as it were, that might be useful for this purpose as scaffolds and fantastic.
And this person David Baker in.
Wisconsin. I think the Wisconsin legacy and Washington.
Yeah. Uh, I think it's Washington. You have to check that.
Anyway, he is another person is on my short list, actually, as a structural biologist.
And he. Takes proteins that have the capacity for being a subunit.
Usually that might be trimeric I say,
and it looks a bit like a pyramid and then fiddles with the three ends and get some stick together and they assemble really beautiful work.
He's done a lot of that and he came up with one particular one, which is an enzyme from a bug in the Deep Sea Events course at Toga Maritime.
And I think it is that an enzyme that's involved in sugar metabolism in that organism, but it does a reaction which isn't, doesn't happen in us.
So um, uh, he, he got this to assemble and it's basically a trimer.
So it's three stuck together in a pyramid shape.
And when they assemble, they form a perfect dodecahedron turducken, a 12 sided figure with each side being a pantomime, a perfect pantomime.
Well, I think they're perfect Benjamins. And of course, this is Euclidean.
I mean,
this is in book 13 of Euclid the present they they do dictionaries described it has various extremely interesting properties in terms it's got the
golden ratio all over it it's got it's a it's got packing maxima so you can pack more into that space than in any of the other figures in in Euclid,
as I understand it. So it's better. It's it it's packing.
It can pack really effectively. And it has because it each of these is a trimer.
It ends up with 12 containers, 20 APC's and each apex has got three of these things in it.
So he's stuck what that so and he showed that you could put fluorescent proteins at either end of the
trimer and the thing would still assemble so you can make these very very fluorescent particles.
Spotted that and realised that he could put the catcher part one half of this bit of protein on one of
the ends and then you have a particle and if you put the tag the other bit on any protein you wanted,
then you could just stick them together and all the difficulties of making specific particles would be solved in one simple, very simple thing.
So he did that and it worked. It's you can assemble proteins onto this particle by just sticking the SPI tag.
He calls it spy catcher and spy tag spies because of step by origin is we've been asked not to use the
word spy because of worries about conspiracy theorists and the government spying on us through vaccines,
all that sort of nonsense. But, uh, so that worked.
And he told me all about this. This breakfast. Oh, you know, it's absolutely amazing.
And he wasn't studying flu, so I said, Well, should we study flu together?
Because more complicated with flu, because the two key proteins haemagglutinin,
it has got three units stuck together and the the other key protein and it's got four units stuck together.
Now the ends of these three are all I'm just going to say that will slowly for the benefit of the transcribed neuraminidase.
Neuraminidase is an enzyme that's on the surface of the flu virus, which actually a flu virus binds to a sugar called sialic acid.
And uh, in order to be released from an infected cell, that has to be chopped, and that's chopped by the near minute.
So the names are a little bit crazy because but we're very bad at names in science and so and so.
But these are both important proteins for flu because if you make antibodies to them,
those antibodies can be protective and they either prevent the virus getting out if they block in your amenities
action or they prevent the virus getting in by stopping the haemagglutinin from binding to acidic acid.
And that's quite apart from what T cells do. And antibodies of course can actually prevent the infection ever getting into you,
which is better than even the T-cell because the T cell only kills cells once they've been infected.
So so I was very interested to see what would happen.
And my worry was that if you have a protein with three of the SPI tags on it and you've
got a particle with 60 places for it to bind and another particle next door with 60.
But instead of binding to this particle, it might bind to that part.
And then you might end up with a lattice which would just come out of solution
and that would make a mess and might be very difficult to use a vaccine.
So we did a whole lot of experiments together over a couple of years with him in Germany,
and then he came up with a whole set of other proteins that had multiple attachment sites for the spy tag.
And basically the nice thing is that actually it works fine as long as the three sites are close together, they prefer to bind to one particle.
You do get a little bit of cross-linking, but very little.
And the only time you really get crossing is if they're sticking out at either end of a, you know, a dime or two things stuck together.
And then you did get a lattice forming. So that was a very technical paper.
And and we published it and that gave us all the technology we needed to now do things properly or not properly.
And we did it very properly in that paper, but to actually do things in a a applied way for a particular thing.
So we were working on flu and the flu.
We're particularly interested in the neuraminidase because modern flu vaccines don't really have much neuraminidase or it's very,
very amount it's not regulated against.
And yet we now know from really excellent evidence that if we had a good antibody to neuraminidase,
that would add to the protection of the flu vaccine, which, as you know, is not very good.
It averages about 50%. It can be worse or a bit better. But if we really had good neuraminidase antibody, that might bump it up, you know,
to regularly more like 60, 70%, which would be a really valuable thing.
And the important thing about the particle, because it's been known for many years that if you immunise the neuraminidase protein,
you can get some protection, but the particle makes it more powerful, so you need less of it.
So if you've got a problem with production and you know, you may be able to use ten times less to get an effective vaccine.
So that's the benefit. And in terms of its transport ability and use.
Yes. Now for neuraminidase, pneumonia is a complex protein.
So as we come on to the covered version, the COVID version, you can freeze dry it like coffee powder.
But we haven't tried that when you're Amanda, is that that's a big ask because it's a very complicated protein.
And if you freeze dried it, I have a feeling you might end up with something.
It wasn't active anymore, but we will do that. It's part of the project, but you don't have to keep it in an 80 -80 fridge, all that kind of.
Well, we keep everything in -80 fridge until we know that we don't need to.
So at the moment, it's all in the mind. Ten -83. Yeah.
Okay, so let's, let's get onto it. So I'm asking everybody this.
Can you remember where you were when you first heard that the looked as if there was a pandemic developing?
And how soon after that you thought that was something that you and your colleagues might jump into?
I think we were here in the lab chatting and it became obvious that there was and I mean, we had a sort of a very early warning because,
you know, the institute has a long running collaboration with China, which David Weatherall set up many, many 30 years ago.
And it's been incredibly productive.
Uh, we, we've had many, many Chinese students have been very successful, including George GAO, who's now, you know,
very senior in the scientific administration in China, who is a brilliant scientist, structural biologist and and virologist.
So and I'm I'm very fond of George and whenever possible, I mean, he's incredibly busy now.
We talk and we've done some collaborative work together on flu on their many days actually.
So we had warning because he basically told us that things were not looking good and that
was about the time that the first sequences were published and doing something like that.
Yes. And a structure was well,
we already knew the structure of the Salisbury related cells protein and we're pretty certain that this would be very similar.
And I think a structure came out very soon afterwards and very clearly very similar.
And it's a trimer, um, the flu, the virus is an RNA virus.
So it's, you know, in a sense not so dissimilar. Well, it's very dissimilar to flu, but it's, it, it's of that family of RNA viruses.
It, um, uh, its surface protein is a trimer, as you would expect.
Uh, it was highly suspected that antibodies to that protein would probably be protective.
It wasn't. I mean, obviously at that stage we didn't know and we didn't know what the receptor was at that stage.
Um, but uh,
what was known is that from SA's you could extrapolate and from SA's it was known that the there was a thing called the receptor binding domain,
um, which forms in our minds it forms a kind of a squirrel shaped.
Blob mannequins. I would look out of my window watching the squirrels eating my bird feed, which was driving me up the wall.
And they were sitting there looking at me and I thought, Gosh, that looks just like the IBD.
So that helps us just remember the anatomy of the molecule and it was already known some very nice work.
Peter Hotez is group and people surrounding him that you could that that unlike flu that receptor binding domain folded on its own.
So you could you could express just that in in eukaryotic cells and it would
fold bind the antibodies and work to the vaccine for cells in animal models.
So we already knew that and we were very suspicious that the same would be true for this.
So when the structure came out, there was something that looked exactly like the receptor binding domain.
And I remember sitting here with Pramila and Jack and looking at it and saying, well, that's,
you know, let's let's just make that and stick it on the particle and see what happens.
So we were we immediately saw a way of doing this.
We were a little bit making a bet because we didn't know what the receptor was at that stage.
And we didn't really know that this was the receptor binding domain for this virus.
But it was a reasonable, you know, assumption. So I'd have to look at my notebooks to find out exactly what day we actually got started on it.
But we ordered the sequences and designed something where we put the spy tag at the front.
I mostly put things at the end. I don't know why, but I've always rather like put them at the front.
So we had the signal sequence smarter than we had the the receptor binding domain and then something to help purified at the end.
And that was the first design and it just worked straight off. It expressed really well.
I mean we were surprised at how well it expressed and it assembled on the particle perfectly.
And it's a monomer, it's just one. So there's none of this problem of it possibly crosslinking this or that.
And the particles were highly immunogenic and we showed that they were very, very stable so we could freeze dry it and then thaw it.
And it was just as good. So there's no turning for cold chain.
You can just send it through the post. And in fact, when we tried to get various people to help us with an animal model and we
couldn't get it in in England and the only animal models were at Porton Down.
It's huge long queue and very expensive.
I mean, horrific, expensive. And we weren't getting any funding, so we had a little bit of funding from the University Fund,
but it wasn't enough to cover that which was going to require £400,000 or something.
So I did what I usually do in these circumstances. I rang my mates in America because every few years I go to NIH and I talk to the vaccine group.
They're just not by invitation.
I kind of thrust myself upon them, as it were, because they're always enthusiastic and you always get a fantastic discussion.
This is the National Institutes of Health. Yes. And I did so.
I did the same through John. You know, he's an old friend.
I said, you know, we'd love a bit of discussion. And he I'm not sure who he spoke to.
But anyway, the next thing I knew, there was a panel discussion booked by Zoom with lots of fantastic people on it.
And I just said what we were doing. And, you know, any advice and any help you can give us?
So I just thought maybe this question ought to come up later, but it's the thing that immediately comes to mind.
Clearly, all the vaccines were developed around the world. Yes.
The money was poured into those. Yes. Why did you struggle to get funding for this?
Was it just because it was a novel mechanism?
Whereas I think you'll have to ask the UK either because I find everybody with an existing platform that already, I don't know, maybe I'm getting old.
I don't know. But I did try and talk to everybody I could and I pointed out that this was very easy to match to any new any new variant.
Very simple to make. You need very low doses, you know.
But we just didn't get anywhere.
I think the problem was that at that stage, there were a lot of people shouting their way, as, you know, advertising their wares.
And Oxford, obviously, that Jenner were moving forward very rapidly with a very successful vaccine.
And I think the attitude was, why would we want to spend a lot of money on an untested technology at this stage in the pandemic?
And I can sort of understand that argument. It's very short sighted, but there we are.
So we we persisted.
And the the next step was to make it cheap and quick.
So again and this is something I've always believed in, talk to people.
Don't keep it quiet. You know, and we don't we haven't tried to patent any of this.
So then and we haven't.
I mean, some later down the line have. But so I, we work with absolute antibody quite a lot.
Absolute antibody at that stage. Absolute antibody was founded by groups of excellent biochemists from Oxford who patchy Oxford but
a bit fed up with Oxford administration and formed their own little company to make antibodies.
And they've been very successful because they're very high quality and their quality control is good.
So when we wanted a lot of the particular antibody, we'd ask them or other things.
And at that time we were also working on producing a very simple test for antibodies to COVID.
And that's another story. But it's one I'd like to tell. It's quite nice. And they were making the reagent for us.
And in Wilkinson, who was the senior scientist there, I was telling him what we're doing and what when,
because sometimes if you explain what you're going to use it for,
they can give you a very good advice about what level of purity you ought to go for and so on.
So I was talking to him about it and they explained it to me and what's really interesting and talked about the particle and everything else.
The next thing I know, I get this call from a chap from the CPI and Chris Oh, this will be terribly embarrassing.
If I can't remember his surname, it'll come to me in a moment. I'm going see now.
So CPI, the Centre for Process Innovation.
Now I had never heard of them.
They are funded by government funds mostly and their role is to have a very wide range of technologies, help people develop a technology to a product.
So they help with they can investigate, scale up its complications of that.
And I got this call from Chris. He said, I hear you.
You're working on a COVID vaccine.
And and because I'd said to Ian, you know, we'd really like to make it in yeast because that would be cheap and quick.
And he said, I can put you in touch with people who work with yeast.
So he put me in touch with in Will Ian Fotheringham,
who is head of a company called Engender that are real specialists in yeast protein production, amongst other things.
And he's a wonderful chap and I had an absolutely delightful conversation with him,
the his his sort of senior post-doc and Chris and they said, Well, why don't we just try it?
So then Jak and Leo sort of worked together and we,
we tried the very first construct and it worked sort of 90% to our satisfaction because we ran into a slight problem
that the original group working with sales had run into that when you're trying to express this thing in yeast,
the yeast has a very simplified well, it's not simple, but it's simple.
It appears simple to us compared to the eukaryotic system for adding sugars to proteins.
And occasionally it seems to go into overdrive and add a huge long chain of mannose is that you don't want.
And we realised that it was doing this and this was upsetting the ability of the RBD to assemble it.
Didn't block it completely, but it was definitely interfering.
So we then worked out which sugar it was by which side, and it was right at the beginning of the, of the second.
So we just chopped it off and that solved the problem. So we haven't had a problem since.
So we make it in yeast now. And the great thing about that is that you can theoretically make huge amounts.
There are very well-defined, you know, GMP processes for making it clean for vaccine.
So we now had production of yeast.
The yeast version worked, so we sent that to an idea and they showed that it worked.
And so we had a production method. Then they did very clever things with the particle.
So the particle was being made in E.coli. E.coli makes lots of endotoxin.
No big companies can deal with that and they make lots of proteins and E coli, but CPI and in general were keen to avoid that if we could.
So they put it into bacillus, which is the milk in a milk bacillus bug,
which makes it beautifully and itself assembles and in the medium around the bug.
And so you don't have to break open the bug.
They worked a way of making it secrete, which they have patented quite rightly, and so now they have a very simple way for making it.
So they make that the particle in the bug particles ready made and we can make the RBD the receptor binding domain in the yeast.
And the two things come together to form a very nice vaccine works.
But we didn't have any funding and we tried again and again from UK right now they weren't going to do it.
And then magic happened and that was Pamela Bjorkman.
So Pamela and I have known each other for 40 years, at least from a very exciting period in 1985, 86,
when Pamela was the student in Normandy's lab crystallising the HLA molecule, the tissue antigens, which we knew were involved in virus recognition.
And I had just found that peptides were the final thing that was being seen,
but we didn't know how the peptide and the damage molecule came together and they just
got the structure and I visited the States 1985 and very much wanted to meet that.
Well, I knew Don Wiley anyway from his visits to England,
but to visit his lab and they showed me the structure as it was pre-publication and there was this oddness that there were too many antimony there,
too many ends. And what they'd found was that they had the structure and then there was this blurry thing in the middle.
And I presented my seminar with all the peptide things, and Don said, It looks like this is probably the peptide.
You know, it's kind of obvious. And that was an incredibly exciting moment and turned out to be right.
And we've remained friends ever since. And I often talked about, you know, worked together before.
Anyway, one day the phone goes,
we didn't know by that stage that Pamela was also doing some work on this system because she she smart and she'd spotted that it
was really powerful and they'd done some work with HIV and it was obvious that make putting our beds on would be a sensible idea.
But she'd come up with a very smart idea, which I think I'm not sure if she was the first they were the first group to think of this.
I think there was another group in America who tried it on flu who'd come up with a concept.
And the concept may be older than that. I ought to know how. Sometimes it's really difficult to find the absolute origin of a good idea.
But, um, and the idea was this, is that if you want to make an anti a vaccine that induces very broad antibodies,
one way conceptually is to have a particle with, say, up to eight different homologous components from different viruses.
And then when the antibody comes along in the lymph node, if it can bind.
Across two of these things that the tape sees that we're talking about, it will have an advantage.
It will be stimulated more effectively because it can hold on for longer.
That's the idea. And so the signal, the B cells will get the signal, whereas if it's only wholly owned by one arm,
it can fall off and it won't get such a strong signal since they've called it avidity advantage, avidity, meaning stickiness.
It's a really neat idea because it's kind of simple in concept and it's simple to test.
And she put the idea was to see if you could get a good vaccine for bat viruses,
because we know there are, you know, tons of bat viruses out there that we're all worried about.
And so she put eight different well,
seven different bat virus rbds and one coded RBD on there and showed that the antibodies that that particle induced were very broad.
And by this stage we were learning where different antibodies bind.
And there are some regions of the RBD that are more conserved even within the variants, so-called class three and four down the bottom.
Well, basically, if you think of a sitting squirrel, the haunches squirrel and sort of feet down, there are more generally more conserved.
And these antibodies tended to go for those areas. So it was a really, really nice concept.
And so she phoned me up and said, Look, I realise I hear that you've got all these other components in place, you know,
the yeast production by the stage we were talking to Andy Pollard who said, yes, they would do the clinical trial for us.
So we had a clinical trial.
We had really good help from William James in in the Dunn's school, who can do the neutralisation assays on the wild type viruses.
So he's a real craftsman at doing that. So we had everything there said, why don't we join forces?
Well, Pamela is, you know, a fantastically you know, she's a real powerhouse.
And we basically took the grants that I'd been writing for the UKRI and added this concept and sent it to Cepi,
who at that time was saying they want ideas for very broadly Cepi and the.
Oh God, I always forget these the and you'll have to look it up.
It's the Coalition for Epidemic Preparedness Innovations.
I think it is. But you need to check that I hate these.
I mean, anyway, CEPI liked it.
They rejected us. You know, that was one of our other objections before we had this addition.
But when we put it all together, they accepted it.
And so it's a joint grant to Caltech and Centre for Process Innovation in general and US, and also includes the clinical trial in Oxford in general.
So clinical trial, done, school contribution, 30 million, $30.4 million.
Right. And you know, sounds a huge amount of money,
but that most of that is actually going to the Centre for Process Innovation to work up the scale up to GMP and the regulation.
You know, just the regulation is everything is so expensive when you get to that's ten times more expensive.
So just doing things like the various things that the regulators need for showing non toxicity in animal models,
it's amazing the expensive to do that to that level of acceptance.
So but for us it means that Jack's funded for four years and then yeah,
we're going to get a we're just about to start interviewing for an experienced technician health
for him research assistant who can help him because each time we change anything on the particle,
we have to put it through the animal model and check that it's still doing what it says on the can, that we're not missing something.
And we probably do that both in Caltech and here so that we always have confirmation in two labs.
So it's a very good thing to do.
And and then to help pay for the very it is expensive to do all the neutralisation assays on the antibodies with real viruses.
We feel that is important.
We, Pamela, does these so-called pseudotyped viruses which give you quite a lot of answers but they're and for some viruses, that's all you can do.
But in general, they're more sensitive and they can give you a little bit more of a rose tinted spectacle
view of what you've got compared to live viruses and obviously an animal model.
We're actually protecting a living organism. And so, uh, so that all came together and Cepi said yes.
So then there was a tremendously long, protracted business going through everything with Cepi.
And because they they don't say they say yes initially.
Providing you meet all our requirements. And quite rightly they're very strict.
So they have a huge panel of people, consultants who come in and ask to bombard you with questions, quite rightly so.
And we were pretty good because a lot of the basic science showing that this thing looks like it should work is there or done or published.
So it's really mainly the CPI work and then we have to test whatever CPI makes and that's going to go both to thing and a little bit of design.
You know, we originally the design had the original Wuhan sequence in it.
We think that might not be such a sensible idea because everybody who's already primed the Wuhan
sequence may just focus on that and not make the antibodies against all the other things.
So we've changed that for the beta variant, which is quite different and that seems to work fine and we have a very nice antibody against that.
So. And that is just starting.
So the funding has just begun and say, we're just interviewing for someone to help Jack to do this cyclic testing of things that come through.
And then we have a bit of money on the side. And I've been we have I have money, you know, a bit of money for here and there to do other ideas.
So one of the things I'm keen on is, of course, keeping the flu work going and we hope to get a bit more funding for that.
Actually, the Chinese Oxford Institute has has refunded, Pamela, to keep that going for a couple of years, which is nice.
And but I am slightly nervous about the variants, the new variants that are coming through,
because they are mutating at a rate we've never seen in flu and they're mutating everything.
So when you look at where the mutations are on your squirrel,
they tended to be over the head of the squirrel and on the sort of saddle area of the squirrel,
because that's where the Ace2 thing binds and that's where the antibodies bind to block the ace2.
So they were clever mutations that actually enhanced ace2 binding while blocking the antibodies binding.
Um, but gradually, you know,
antibodies have been developed with time after multiple vaccinations against the more conserved regions and now they're mutating that.
So that's a real worry for us because to me anyway, Pamela thinks I'm worrying too much, but I tend to worry a lot.
So because our whole concept with this eight mosaic is to make antibodies against these conserved regions,
which works really well for all the bat viruses.
But if these regions mutate enough in new variants, it ain't going to work for the new variants, or it might be weakened.
How can these something as fundamental as the receptor binding domain mutate and still work as a receptor binding domain?
Well, that's the million dollar question. And I'm not enough of a structural biologist to give you an educated answer.
But basically what when, as I understand in my very simple understanding,
is that protein interact and you think it's just one face interacting and fitting against another face.
It's much more subtle than that, that within that interaction there are hotspots that generate binding energy,
and then there are cold spots where you can vary it quite a lot and it doesn't bother it.
And so it's like that. So there are key interactions which can vary a bit.
So if let's say you had three really strong ones,
you might be able to alter it in such a way that the three different really strong ones, but you still get the same binding energy.
That's the concept. There are antibodies like that too.
So now one of the things that's happening, as we analyse more and more antibodies, there are antibodies that are binding.
Originally, the antibodies that bound on the head and these regions were blocked.
All variants that just lost recognition, most of them lost recognition and tonnes of papers claiming the next antibody that was
really cross-reactive and the next variant would come along and block that antibody.
But there are some that are amazingly cross-reactive that still bind in these regions and they're doing the same thing.
They're able to tolerate changes, but they have like a grappling on, as it were, that can bind to a to a dispersed epitope.
So we think of epitopes as being an area of surface to which the antibody binds as it's more subtle.
So you can have a sort of dispersed set of conserved residues which will allow the binding and and of course,
we should be able to stimulate those antibodies, too, with this mosaic concept, which we're hoping we will.
But on the side, one of the things I do want to do now is there are so many variants you could make a mosaic of variants and see how well that worked.
And it's easy for us to do because we've got everything in the freezer. So I do want to do that as we.
So we have a back up plan in case we run into the problem that the antibodies we
generate in people when we we do immunise them turned out not to be so good.
The latest variant which may have mutated all those regions.
So it may turn itself into a virus which is so different to all the bat ancestors, you know, that we run into that problem.
But, but the concept that Pam's come up with, Pamela's come up with.
Is very powerful and in principle you can apply it to other things.
It really works best for small monomeric units like the RBD.
So we're very lucky that this virus is tailor made for this for this technology.
Flu or HIV is much more difficult.
So that was a stroke of luck. And again, it was something that drove us and we tried to get that message across to the funding agencies.
Look, this is the perfect technology for this.
Don't need a cold chain can update very quickly can make it in yeast even if we didn't have the the mosaic concept and still they didn't buy it.
I don't know. But I've never understood funding agencies that there are periods in your life when you just you showered with money.
So at some point I just had so much money, I didn't know what to do with it.
And then there are other times when the work you're doing seems to you to be just as thoughtful and valuable,
and yet you just can't get anybody interested. It's our business.
And then I think funding agencies I mean, I might say things that people don't like now,
but I've noticed over the years the funding agencies become dominated by administration rather than science, and the MRC certainly is like that.
And these are very good administrators, they administer very well, but they shouldn't be developing in their science initiatives.
It should be the scientists doing that. And I do worry about that.
I think in the UK I just huge administration and everything's in one place that's bad.
You need diversity of funding. So I, you know, but I'm retiring soon.
So but I think for the future and this obsession,
that problem and the obsession with spinoffs and secrecy and patents, that means people don't talk as much.
And that means you will not get the Nobel Prize winning work. You can use up all the previous Nobel Prize winning work you've got.
It's like spending the family silver, but coming up with the new things you won't.
That will happen at a lower frequency if your institution is obsessed with this sort of thing and with what I would say,
fashion driven funding agencies, which tend to go for the big groups, fashionable stuff, they're all sitting on, all the committees and all that.
And you need you need some, you know,
benign dictatorships to pick out clever young people and give them funding and have faith
in people and not allow this sort of political stuff to to have too much of a role.
So I personally would revamp the MRC, gives them plenty of power and have it much smaller scale run by scientists with true civil servants,
helping them to run it rather than taking over the running, which seems to me to be what's happening.
I'll get into terrible trouble.
You mentioned Tesco so the this the vaccine isn't the only thing you've been doing in relation to go with you mentioned testing was another yes.
So so worked on. Yes yes. So in I think April of that first year I got a call or an email actually from a very interesting chat.
And, uh, could attend. Um.
What is it about settings that's going on? On my sister, wasn't it? Etienne.
Anyway, he called me and said, Is anyone making an antibody test?
Cheap, easy. And.
And he said, you know, the obvious would be haemagglutinin, which is the old fashioned way of detecting antibodies that are glutamate red cells.
You know, Coombs and Kim's test and the application to infectious disease, which up until about 1966 was the way to do it.
And, uh, and so I listened to that and I thought, well, why not?
You know, we could have a go at this because the RBD is so malleable we can use it and probably attach it to red cells.
So we thought about it.
We did some brainstorming together and found a paper from a Paris group some time ago had shown that they made a single chain antibody.
So from a dromedary and from a molecular biology point of view, they're easier to manipulate.
And that binds to like a foreign on red cells to a conserved bit of like a
foreign like for foreign polymorphic and varies between individuals quite a lot,
or at least in geographical areas and so on.
Anyway, this thing bound strongly to do like a foreign.
And so looking at the structure, it looked easy to just link the receptor binding domain to that, like a foreign binding unit.
And then that should bind to red cells. It shouldn't crosslink the red cells, so they should stay in solution.
And then if you had an antibody that would bind across the red cells and cause it intonation,
which you can see by I, you don't need a very expensive machine and you can titrate it and so on.
So again, we just made it and it worked. First time bingo, just straight off, the very first design worked.
And so we published.
We had to do a lot of control experiments to show that it was real and in know artefact,
you know, but we had all these nice monoclonal antibodies we can do it with and so on.
So I wrote that up because I actually did most of that myself.
I set the assay up and then Pamela and Liza, who's not here today, and we did a lot together and published it.
And I spoke about it to the W.H.O. and said, Look, we're prepared to give this away free because it cost us.
We worked out that it was something like 0.0 $0.07 or less than a penny per test, basically at the simplest level.
Whereas, you know, for any other type of antibody test, you're talking two or £3 a pop for every single one.
And and so we published it.
And I worked out that because I run a little charity that's based on my Jonty prize, which I put into a charitable trust.
So we use that money generated by the trust.
It's just it's for medical research, but we can do any medical research.
So it worked out. We could easily fund people and give them 20,000 tests straight off.
And if they did something interesting with it, we could go on providing it. So we've done that.
And that's proved quite interesting because there's a wonderful person, Nilka, who got a voucher,
who trained here with in the department and now is a senior person in Colombo, and she's done a lot of work with it in the field.
So it really does work in a real place.
And actually I mustn't forget it because he suggested this and he got me going on it and we worked on it together.
You're a senior author on the paper, and then we talk a lot to a group in Bergen.
Dr. Cox, Professor Cox.
And they were interested because they do a lot of fieldwork in Tanzania and they wanted a simple test because again, you can freeze dry this reagent.
And so we sent them lots of stuff.
And by that stage, we were comparing the levels of antibody you could detect with neutralisation assays.
And actually it correlates really very well with neutralisation, with the big study, with the haematologists here.
And and they wanted they did a basically we confirmed each other's work in different cohorts and they did a big cohort.
And William did the assays for us.
They had neutralisation assays. And we, we then looked at different variants and it looked, you know, it's a very good, simple antibody.
You just take a fingerprint, you can do it with. You can do it from a finger prick.
At its simplest, you take a finger prick or a blood sample, take a serum or plasma.
Doesn't matter. And and the indicator cells can be O-negative cells from the blood banks.
Those don't react with anything in the serum.
But some parts of the world, O-negative is a very rare blood group,
and those are the kinds of parts of the world where this test might be quite useful.
So you can do it with the person's own red cells.
And the two ways of doing that, you can just dilute the blood one in 40 and add the reagent,
and that gives you a a plus minus test at one in 40 and or if more clunky.
But you have to wash the red cells to free them from any antibody and then you can use them just like you would the O-negative cells,
because it's their own blood. So they're not going to make their own red cells, and that works fine.
And that's how we do it in the lab to find out each other's levels. And that's been quite popular.
I mean, we've sent it out. We've sent out about 30 or 40 aliquots around the world.
Of those I mean, what happens when people request these things is that I'm afraid about 90% of the
time it goes in the freezer or into the fridge and never comes out again because,
you know, the relevance begins to wane because now that probably 90% of the world are positive for antibodies.
What's it going to tell you? Of course, it might help you tell who's going to get seriously ill or not,
because if you had an antibody level above a certain level, we haven't been able to define that.
But if we had if we knew that and say, well, if you've got this level against this variant,
you're not going to get sick, that would be quite useful, I think.
And for elderly people, you know, I was I had these pipe dreams of of the visiting, you know, in some parts of the world,
like we were hoping to do some work with Cuba,
but it was impossible because American the American customs wouldn't allow us to import the reagent again.
It was impounded. I mean, but they've done very well because they made their own vaccine.
I have to greatly admire what they've done. And then they were interested.
So. So you get people who are interested and then they can use it because you don't need equipment.
Just hold it up to the light and you see where you've got your agglutination and that's it.
And so Burgin have done a lot and Natick has done a lot in, in and in Lanka.
And we've got a colleague in South America in and, uh, where is he?
He hasn't published anything. They keep sending us bits of data on his hospital staff, basically, and so on.
But it hasn't. I mean, it's not like there are 20 groups using it.
There's maybe five, maybe more, maybe some we haven't heard of.
We had a visit actually from someone working in in Africa who's used it and he's adapted it slightly.
And so there are people and every now and then we do say to them, you want more,
we'll always send you more, because we it for us it's incredibly cheap because we might.
The charitable organisation pays for it and we either make it ourselves and send it to them or we get absolute antibody to make it.
And. So that's been fun. Not game changing, but at least it's something that's for people working in countries where they have literally no money.
They can do research with this and get some information.
And in the early days, it was quite useful for telling what proportion of people had been infected.
So in Colombo, of course, in the poorer areas it was very high.
50, 60% of people were seropositive, whereas in the more affluent areas it was lower, so and so on.
Yeah. And I also had a note about therapeutic antibodies.
Yes. Yes. There being antibodies. Yes. Well, and we were making lots of monoclonal antibodies to flu.
And then after we thought about making them ourselves here,
but we were doing so many other things because we got all the technology and everything and we thought about how to do it,
but it is very labour intensive. One other hung in Taiwan.
This was a student here, but Arthur got going on it absolutely immediately and was actually really one of the first
people in the world to isolate monoclonal antibodies and was sending them to we had a sort of
arrangement that he'd send them to us and we characterised them on the different variants and
over weren't variants of that stage but on virus and neutralisation and that and but we were,
we were not it wasn't the foot was not full on the accelerator because we wanted to, you know, take our time over it.
So his paper was published rather late and lots of other people, of course, were doing it.
And Gavin Scruton has done a fantastic job.
He really focussed on it and he has a group of really, really skilled crafts and around him craftspeople I should say.
And they've done a fantastic job as a series of papers.
And so looking at monoclonal that define the different variants and the escape and everything else,
working with structures with Dave Stewart who helped us originally to this, we did some structures with them.
So that's been very, very attractive as a way of either therapy or protection because as you know,
there's been quite a lot of publicity recently, about half a million people in the country who don't respond to the vaccine.
And we know from other examples like protecting children against and promptly,
but you can protect people with monoclonal antibodies and there are ways of making them long lived.
People done very clever stuff in terms of making them long lived.
So you may only need to inject it every few months and they get protection.
And it's actually extraordinary that this has not happened yet here.
Now, A-Z have produced their combination of antibodies, which up until now looked really strong.
The problem is of the two antibodies in that mix, one now is completely lost its activity on Omicron and the other one is reduced.
So overall, most people find that that combination has got at least an eight fold reduction.
Would that be protective or not? There is some field study work in other places where there are claims that it is still protective.
But I can see I can see the rationale for wanting nice to look at it because you're
talking about a huge outlay of money and if it doesn't work or worse still,
it gives people confidence to go out into the world and then they get infected.
That would be a real disaster. So there are reasons for being uncomfortable.
But what does strike me is that between us, for instance, Gavin, many other people,
I mean, there are thousands of antibodies that would be protective against Macron.
Why on earth are we has it been so slow?
And the reason is, of course, regulatory issues are huge.
Things need to go slowly. It needs to go through a monster range.
But we need to revise this because if you're ever going to use antibodies during a pandemic, we need a quick way of doing it now.
Many years ago now, ten years ago, I got a meeting together with the MRC to discuss this very issue and a few,
you know, we got some really good talks,
nobody showed the slightest interest and we had a big meeting with one of the big antibody producing companies
and actually went to the regulators at the time to discuss making them quickly what would regulation require.
And it wasn't impossible. I mean, it could be done and you could actually have everything done probably in a few months or even less.
But it somehow isn't happening.
And for it to all taken this long, I mean, Arthur has a pair of antibodies that would definitely protect against these.
Everything in vitro would suggest that, and I'm sure Gavin does to lots of lovely antibodies.
Why on earth isn't there a system for doing it quickly?
And my pipedream again would be that the, you know, the NHS makes.
Its own blood products. They have five factories that do this very, very effectively.
And they they distribute them around the world. They could make these monoclonal antibodies.
You could have a you can have a whole production system nationalised in the NHS and you could switch quickly could you.
If you. Well I believe you could. Yeah, I believe you could but you'd have to have a regulatory system for accepting a change and accepting that
when you change something there's obviously a very small risk that it's going to have some idiosyncratic,
unpleasant effect on somebody. But the likelihood of that, given the overall experience, I would say, is pretty low.
Now, is there to the some of the best people in the world?
I mean, the Cambridge group have produced tonnes of therapeutic antibodies.
So if anybody can could work out a way of doing it quickly, it would be them.
But it seems to me that it's one thing producing an antibody to treat cancer or treat an autoimmune disease because it's there all the time.
You can spend years getting the regulation right, but when you've got something like this,
it needs to be done quick and we need to work out ways of doing it quick.
And it's not impossible. It's entirely possible because you can make grams of antibody in a week, you know, within modern methods.
But we need a we basically I think you need a whole different regulatory set up for this setting.
And so we now have all these institutes for pandemic preparedness.
Whether they are to tackle this or not, I don't know.
I did briefly sit on the one here and the discussions were so broad covering everything from psychology to,
you know, t cell vaccines, you know, you can't do that.
You've got to be focussed. So personally I think you have to be very focussed.
But half a million people needing protection. That's a lot of people.
Yes. Yes. Huge benefit to them, right.
And. So I'm just going to switch a little bit on the personal impact of the of the the whole sort of pandemic situation.
Yeah. You. Yes. So how how did the that the how the the regulations that came in to to reduce the spread of infection.
Yes. Impact on what you were able to. Yes. You and your colleagues. Right. Yeah.
So those we have an excellent biological safety group here and of course, the university.
And there was basically a dispensation.
If you were if your work was directly relevant to the pandemic, we could go on working, providing we observed very particular rules,
obviously hand washing, all the usual things, the masks and preferably the FP twos and a white coat and everything and separation in the lab.
So I think we were only allowed to people in the lab at once. And and we stuck to that obviously, and we were inspected and everything.
But because I mean, Pramila and Jack are powerhouses.
And so we worked out timing and everything. And then Priscilla was had had her baby.
But it just amazing how much work someone can do.
There's no distractions and no seminars. And then, you know, of course, it's all on Zoom.
And we had regular meetings by Zoom or if I was coming in, I tended to be a sort of troglodyte and come in at night or on weekends,
and we talked regularly about what was going on,
had regular meetings with with our colleagues and with Pamela and everything and all worked that worked very well.
The Zoom meetings worked very well, actually, and Jack got a huge amount done for me.
I got a huge amount done. You know, all these collaborations going somehow it worked and it reminded me of when I first came here and when I
just finished my PhD and Peter Morris very kindly cut off one end of his very big lab and gave it to me.
He said, That's your lab, and I could organise it exactly as I wanted and I no distractions.
So I worked and Francis Scotch and we let Francis Scotch work with me.
He was again fantastic. And we, we had the incubator gels pinch running this or that and I had a chair like this with
wheels on it and I could just move around and we got the huge amount of work done,
just the two of us, and that that's what happens.
If you can really focus and you're not constantly distracted with committee meetings and this
and that and going to this seminar and making sure you've been out to lunch with this person,
it you know, and I think the students had it tough.
So we we have a new student just starting it in the middle of all that.
And I think it's been hard for her, but we've tried very, very hard now to have regular twice weekly meetings.
Actually, we have a lab meeting always. Everybody has a should have show and tell and and then we have individual meetings
and and I like with the Dphil students to in the last sort of period and it can
be longer or shorter depending on how they're doing and everything else to have a
weekly thesis orientated meeting to begin to plan out how the chapters will look,
what the overall point will be, and so on. And that way it's much easier when it comes to actually writing it up that it's have rules in place.
I'm sure it's but I mean it's like writing a book.
It is a book and it can be a very pleasurable thing to do actually if, if there's lots of nice data and so on.
And so we're trying to do that and yeah, mean that all sounds quite positive.
Do you think any of those the lessons learned from that can be continue to be applied now things are, as it were, back to normal.
I don't know. I mean, human nature doesn't tend to learn from experience very much, do we?
I mean, we we do. But by the time you've learned it, you're retiring.
And and this university,
we're quite good at respecting the retired group of people who do come back and remind us about lessons that happened in their lifetimes.
But even then, we don't tend to listen. We tend to always make tend to go around in the same make the same mistakes.
And I think it's inevitable. I think gifted people learn from their mistakes.
It's the it's one of the key features of the most gifted people.
And and they're not afraid about making mistakes.
And I was talking we have a visitor here from Spain for the summer,
and he's done a project which I was quite keen on and I'm still keen on, but the poor chap has been clean negative.
We had an initial positive looking result and he's gone through, done everything perfectly.
I mean negative, you know, it's very disappointing, but that's life.
My experience is that 90% of the ideas I've had for projects don't work or go wrong or, you know, there's some problem.
And that's the way it is. And that's what, again,
if you have a granting agency that's only run by essentially is run by the administrators who only understand positive results, they don't get that.
You know, you've got to fund things that have a high chance of not working.
And one of the reasons I think they stopped funding project grants for young people was that they said the yield was so low.
That's a good thing. That's science. That's what it should be.
Yes. And giving all the money to very big groups run by people who don't do practical things anymore.
I mean, I worry about senior scientists sitting in offices and aeroplanes.
They completely lose touch with the reality of how difficult it is and how how gels go wrong all the time.
How these experiments are not easy takes craftsmanship and they lose.
I think they don't twig that that the craftsmanship is the key thing.
And and certainly people who've only done a very little bit of science and then become a scientific administrator,
I don't I think most of those people don't have that in their bones, you know, and and that so failure is part of success.
You don't have to be incredibly lucky to do a project that's a huge success and get your niche papers and everything just off like that.
I mean, it does happen and it goes to people's heads and it can be a very bad thing because because the likelihood is that the next five years,
again, to be Barry, you know, will be tough if they're trying to do interesting things.
So it's just the nature of it. Um.
So did you. Did you? I mean, I know you've been very unwell in the past.
Did you feel personally feel threatened by catching the virus?
Well, I you know, I looked at the statistics, so at the beginning, we were told that if you are hypertensive and overweight and over 65,
you had a 10% chance of ending up in ITU and maybe, maybe a few percent of dying.
And I fitted that demographic completely at the time.
So I thought, well, the first thing I got to do is listen weights. So I did that and I just behaved sensibly.
We, we avoided contact and I did all my Zoom meetings.
I came into the lab, but I made sure that we were really careful.
Nobody got COVID at that stage. And so from that point of view, I wasn't too worried.
I mean, I thought, you know, being in a place, you know, where I have huge faith in my colleagues,
I thought, well, I probably wouldn't let me die and I'd probably be all right and I'm quite fit.
Otherwise, I got over the cancer. I don't have immune deficiency and I just thought I was overweight, so I needed this weight.
So I did that. But, uh, so I wasn't, I wasn't frightened in that sense.
I just thought, you've got to be sensible, um, which we did.
And then the vaccine, you know, I did get,
I had periods when I sort of wrote to lots of people because I did feel I did feel that some of the things that were being done were bonkers,
you know? I mean, I didn't like the idea of deliberately infecting young people with the virus experimentally.
I think now it's maybe slightly different that we've got various treatments and so forth, but at the beginning you mean challenge studies?
Yes, challenge studies. I was very against it.
And there are all these philosophers of science saying they thought it was all right, but they were all over 65.
Would they be happy for their children to be in this with a 15% of roughly 15% long COVID?
And we didn't know what that was.
And and I felt that we weren't going to learn anything really from it because the people who get sick or the old people and
you're not going to deliberately infect them and the young people don't get this horrible inflammatory reaction in their lungs.
So what are you going to learn? I thought it I just thought it was the wrong thing to do.
And when I tried to talk to people, they wouldn't talk to me. I mean, I wrote to the people doing it here and they wouldn't reply.
You know, I was very upset by that. And I lost my respect, actually, for someone who's who's backed it.
And I cannot see well, I've never been convinced. And one of the senior ethical people here, Tony Hope,
initially was in favour of it because he'd been sold the argument that a small
risk to the individual being affected was worth the big benefit for humanity.
That is a very, very dangerous argument, as you can.
You know, I think that's a terrible argument. But I went through it with him without saying what my thoughts were.
I just went through the facts and he changed his mind.
He said, I absolutely agree with you that there is a risk.
It's all about the risk level for the individual you're infecting and not the benefit that might come out of it.
And and the risk level was too high, but they claimed that it was safe and they claim there wasn't anybody who got long-covid and so forth and so on.
But the principle it was the principle. I thought it was wrong.
And I don't think we've learned anything value from it personally.
But so I got worked up about that and I got very worked up about the reduction of restrictions,
I think, in 2020 and then all that eat out and stuff, it just idiotic.
It was like leaving burning coals in a dry forest when there's a wind blowing and saying It's all right now and just walking away.
Because it was absolutely clear if one of a thousand people still had the virus, very soon, it would just and it did.
And that, you know, a lot of people died.
Now, of course, we see it just the biological angle, not from the whole picture of the economy and all of that.
And but some countries managed to hold on to lockdown until the vaccine was available, and that would have been biologically the sensible thing to do.
But, you know, so I did find myself I think some of my friends thought I was losing it.
Sometimes I think it was I wrote them. But, you know, we've got through it.
But I'll be very interested to see, you know, with this with this review or investigation into how everything was conducted,
what they come up with and how politicised that will be, you know, because obviously there was all the nonsense about contracts and so on.
People basically had this chicken behaviour.
But uh, to me, I mean I think we could have done much better in terms of locking down that because lockdown,
the principle is if you're separate, you're not going to infect people. So but to allow big sporting events to go on when we knew there was terrible
trouble brewing and the whole earlier attitude did seem to me terribly cavalier.
And and and the. Yes, this notion of herd immunity that was going down into the well, the concept of herd immunity is fine.
It is that if you let's say you have mild, mild, a mild illness and everybody gets the mild illness that gives you herd immunity.
The problem is it wasn't a mild illness. And the people advocating this were basing it on wildly optimistic view.
And there was a person, his name I probably shouldn't mention, but who gave it at a talk?
And, you know, we said, well, how can you possibly, you know, justify that when we know that something like 1% of the people,
at least 1% of the people who catch this illness over the age of 60 will die.
You know, and and then the epidemiologist did the calculations and went to the primaries and said,
look, you're talking about 400,000 deaths if you pursue this. And I don't know all the details.
And, of course, I mean, emotions were running high,
but I got the feeling that number ten were almost sifting advisers for those that said what they wanted to hear.
That was my impression, of course, that that would be totally denied, I've no doubt.
And there were some people saying things that they were not qualified to say.
I mean, no doubt about it. And, you know, in my view, you know, it's just my view.
And so but I think I mean, we wouldn't have known that at the time, but in fact it hasn't behaved the way other waves of infection,
epidemic waves, uh, in the, the, the possibility of becoming reinfected seems to be quite yes.
That sort now. Yes, it's been that, that has been a surprise that despite having quite high antibody levels that the new
variants are able to get through the antibody wall and give you a moderate infection.
For some people, it's not so moderate, of course. So I think the last thing.
That's 900 deaths per week of people with COVID now.
How many of those 900 are due to COVID? I know that's the argument, but it's still a some of them are.
And you mentioned you yourself had been quite unwell having been vaccinated how many times?
Oh, I was back in 93 times. Yeah, I lost I lost three kilograms in weight and I've only just recovered that.
That was about two months ago and I was Yeah.
Knocked off even more than usual for four.
But, but, but you know, that's better than obviously ending up in hospital.
Yes. Yes. And but but it's across the country, repeated across the country that level of absenteeism.
Huge. Economic. Huge. Yes, huge. Yeah. No, I think it's always easy to be critical and it's easy to sit in one's, you know,
in one's academic from one's academic position to see that in an ideal world with an infinite resources, how you might do it differently.
Um, and of course we don't have infinite resources and those, you know, economic collapse is not something you, you want.
But, but at the time the argument was really the NHS collapsing because that would, that would have been utterly awful.
And so yeah. Yeah.
I think the whole I think there's a lot to be learned by psychologists, you know, about the way people behave in pandemic situations.
And there are some old stories about this of, you know, cholera epidemics and in big towns and what sort of went on.
And people you would never expect behave in very old ways sometimes in these settings.
And understanding that to some level and being prepared for it, I think,
is part of pandemic preparedness that I think is very important and also very interesting.
What is it that drives certain behaviours?
And I mean this is headless chicken behaviour which is sort of grabbing at straws which you can understand easily,
but more complex things of people pushing themselves forward as experts when they're not experts,
but they're not prepared to admit it, that sort of thing.
And there's a lot of that. I mean, I felt there was a lot of that. Every week the BBC would wheel someone out.
I thought, Well, what authority does that person have saying that?
And the word. And in contrast to that, I think it's probably now felt that people,
as long as they have clear messaging, the population as a whole are much more compliant.
Yeah, nobody expected that whole tearing thing was to me biologically pure nonsense because you either separate or you don't separate half separate.
And then you had this ridiculous business of one mayor of one city complaining about the
tearing in a city some distance away because they had only half as many infections.
Well, that's one one day's worth of viral replication.
You know, it's nonsense. Absolute nonsense. And and the whole theory in the administration of all that must have been very expensive.
And then the testing, you know, test and trace being taken out of the hands of the NHS.
As I understand it, that was mad because they're really experienced and some of the people running the testing have become multimillionaires.
And yet what was the benefit, you know, for us in terms of early diagnosis and so on and all that?
I don't I mean, again, I don't want to talk about it because I'm you know,
I know no more about this than any other ordinary person in the street, really.
But I did feel that there was some strange decision making in that time.
And I think that's part of the psychology of the epidemic pandemic that people do make slightly irrational,
poorly thought out decisions that have huge consequences.
And and how do you prevent that? It's tough.
Maybe you never can. I think we've just about come to the end.
So, yes, this is usual. Final question.
How has the experience of working through the pandemic and the pandemic changed your attitude to your work and or your approach to your work?
And is there anything you'd like to see change in the future?
No, it hasn't changed my attitude to the work because we've been doing what we would be doing,
not in the pandemic, but just rather more of it in the times.
It's been rather more compacted. So we have been very, very busy. But from a scientific point of view, it's been tremendously interesting.
And we've worked with colleagues, brilliant colleagues.
So all these years of scientific friendships and attitudes have come together in this tremendously powerful list.
This we're now called What are we called? I just like referring to us as a collaborative group, but we're all.
They have lovely names for all these things. But I, I, I've enjoyed that enormously.
I've enjoyed seeing Jac and Pramila and Liza, you know, evolve into this and to see all that training and experience.
Being, you know, used in a really productive way and they are very open.
And so all those relationships we've got with Caltech and with the team at Caltech within Genzer and the CPI have just blossomed,
you know, and the lovely thing about all that is there's no paperwork.
Nobody had to sign anything. We didn't have an MTA's, we didn't want an MTA, so we kept, you know,
we didn't talk about it to the people who said, Oh, you need an MTA and that I've known an MTA take a year.
And when the person who's going to do the work in the companies left because the MTA material transfer.
Yeah. Yeah. It's all about secrecy. It's all nonsense.
So lovely thing Ian said we're not doing any of that. We're just going to get on and do the experiments.
And if we if we hadn't done that, we wouldn't be we certainly wouldn't have got funding.
Funding from CEPI. No, this wouldn't have happened. So what's normal?
And as it were, peace time where you could go through all this stuff and you think about the money you might
make by having your spinoff company that will take over is just inappropriate for this setting.
And I think we need to think very carefully about that, that this whole emphasis of spin offs and MTA fees and all this stuff,
which costs a fortune, takes delays everything horribly,
and basically generates mistrust at some level just in these settings needs there needs to be some
legal way of throwing that one out of the window and and then perhaps picking up some pieces later.
People won't. But because you've got to move, one thing you've got to do is you have to move fast and give them that.
You, the Janet team moved very fast.
They were ready because they've done all this stuff with these viruses and we have our differences with them over various things.
But they did move very fast on this and expressing the glycoprotein in an anti virus, which is something, you know, that goes back 40 years really.
They just did it and it worked and, you know, got on with it.
And they deserve huge credit for pushing that forward.
I think they haven't had enough credit for that, I think. But and they will.
So yeah, it's it's being prepared and moving fast and you have to be able to do that and.
So we're slow because we've taken ages to get to this point.
But we hope that this might be a way of dealing with things in the future and.
Um, but it's all it has been extremely interesting. And would I do it differently?
You know, I think one thing that has happened is I thought I would never want to retire and I have to retire in a few weeks anyway.
But I'm hoping to keep going emeritus.
But I there were times and there have been times the first time in my life when I thought would be quite nice to wake up on Monday and just.
Not have anything in the DA, you know, so.
Lovely. Thank you very much. Lovely.