So possible. Can you just tell me your name and your current affiliations?
I'm Annette. Yvonne Bell and I work at the University of Oxford as a translational scientist for the Nuffield Department of Medicine.
And the nephew of Department of Medicine is very big and very large.
So it's a a institute within the nephew of Department of Medicine that is called Centre for Medicine's Discoveries.
That's great. Thanks very much. And without telling me your entire life story, but just summarising briefly,
can you tell me how you got interested in medical science in the first place and how you got from there to where you are now?
It was quite a journey to arrive where I am right now and currently I'm working in drug discovery.
But this was what I've always been doing.
I am originally South African and then my parents moved to Germany at some point and I studied medicine in Germany and.
At that point, I wasn't quite sure whether this was what I was interested in doing.
I also studied music on the side, which I tremendously enjoyed.
But then after I finished my medical school, I got offered a Ph.D. at Oxford in clinical medicine and where I worked on vaccine development.
And interestingly,
actually on the vector that played a role in and I worked on hepatitis C and immune responses and then on vaccine design for hepatitis C in £80 group.
And that was really the point where I got really interested in infectious diseases overall.
I, after finishing my PhD, decided to go back to clinical medicine.
So I had a couple of years of clinical work where I worked mainly as I rotated through the usual
foundation program and ended up working in sexual health and in HIV clinics that I really enjoyed,
and mainly because they were around infectious disease and viral diseases.
And then for family reasons at some point decided to have a break from the clinical training
program where I had a gastroenterology post office and kind of go back to research again.
That was in 2018. So I for about two years worked at 60% for the university and a research position and then addition in addition to that.
And in the hospital, I'm doing sexual health and HIV clinics.
And that at that point seemed to work quite well. Well, for us.
So for me for me personally, in terms of interest, but also for for us as a family, as a as a as a good set up.
At that point,
I had like three small kids and wanted to have a little bit more flexibility in what shifts I was doing and how many shifts I was doing at the time.
So that was a very good set up. And then the pandemic hit.
So that's probably where your next question was.
Well, it's not quite my next question, because I want to explore a little bit more of your your expertise in drug discovery at the moment.
But first of all, there's a question I'm just asking everybody,
which is which what if there was one kind of big question that really drives you in your research?
What would you say was. I think.
What what really interests me is how we can get from a very basic research finding
to a patient and how we can do that in a way that enables whatever we come up with,
whether that's a vaccine or whether that's a drug or whether that's a technology to be accessible to populations worldwide and also relevant.
So how can we make sure that we don't waste our time on something that is actually not going to be used or not going to be accessible in the end?
So it's it's quite, I suppose, quite multi-disciplinary what we're interested in doing.
What, what, what would you say that the main methods and techniques that you use in your research.
So it is quite difficult to nail it down to kind of different methods because it's a very broad field.
Like I've been working in vaccines previously and when it came to vaccines the question
was how do we have to design them to make them relevant to the circulating viruses?
For for breakfast? CURRY The question is actually quite different.
And we're using very different research techniques and different translational techniques to get this drug to the clinic.
But here the of the one big question that I'm currently working on with a very,
very widespread team that works in lots of different institutions and how we can generate the drug that's not working.
And that's a kind of a compound that is basically doing its job and safe enough and all those kinds of questions.
But also, how can we make sure that we can get the compound to the patient in time, in different locations,
and how can we set up and licensing the patents and everything around that compound that.
It is actually a compound that can be given and that is not too expensive and
that is accessible in Bangladesh as well as in Rwanda as well as in Brazil.
The key point so it pre-empts my next question a bit, which is why can't we just label this drug companies is not the.
I mean, traditionally.
Drug discovery has been made in big pharmaceutical companies, and they do have and big pharmaceutical companies come with a tremendous network.
And what they have and that can't be underestimated is an enormous logistical experience.
But on the other hand, all the drug companies have to pay their employees and they run for profit.
And and and they they are mechanisms in place to make sure that patients and in the global south do have access to the drugs.
But all these mechanisms are not quite perfect.
So, for example, the medicines patent pool can provide drugs at lower prices to to low income countries.
But there are some low and middle income countries that are left out from licenses from the medicines patent pool.
And it's the question that I'm working very closely with, and that's like Neglected Disease Initiative at the moment,
is and how can we potentially enable these patient cohorts that are in,
say, medium income countries that may not have access to the very high priced drugs on patents,
but neither have access to drugs on the medicines, patent pool drugs.
How can we enable those to have access to the grants, for example?
And it's. It's not directly linked to the actual research that I'm doing, but what we are trying.
This was a unique experiment that we really run of the pandemic, which was Can we go all the way into clinic for open science?
And we haven't answered that question yet. We're still in the process of doing it.
We've got compounds in pre-clinical development at the moment that are not patent protected,
and we're trying to work out whether there is a way to set up and enough buy in from generic
companies and buy in from governments and buy in from access groups to make these drugs available.
So that's what that's the kind of if you want a more social science problem that is unrelated to actually making a safe and efficient drug.
So you use two terms that which I'd like to spend a little bit more time on.
One is neglected diseases. One, what are neglected diseases and why are they neglected?
So neglected diseases is quite a wide term and I'm covered.
This definitely not one of the neglected diseases of the moment in terms of research,
but I think and traditionally neglected diseases is a class of disease where not a lot of research,
time and effort within pharmaceutical companies has been spent on generating and generating compounds or drugs against those diseases.
So are diseases without a lot of treatment options and diseases where there is
not a lot of translational research ongoing to generate those treatment options.
And and for example, the reason that Drugs for Neglected Disease Initiative in Switzerland exists is to look at exactly these diseases
and make drugs against those that help patients that have these kinds of diseases to actually get treated.
And leishmaniasis is one of those Chagas disease is one of those and then a couple of other diseases.
And I wouldn't say that covered the such pools into this category,
but and neglected diseases can also kind of line up with the neglected patient cohort.
So kind of hold that just doesn't have access to disease.
So for example, hepatitis C virus is not a neglected disease in any way.
They are drugs available and millions of billions of pounds have been spent on on hepatitis C research in the last 20 years.
There are plenty of direct acting antivirals,
but there are still neglected patient cohorts that don't have access to this kind of treatment at the moment,
even though they have been around for a long time. And and actually some of the problem has been obvious for HIV for a very long time.
And you can even go a step further and say they are neglected patient cohorts that don't have access to insulin and diabetes,
like diabetes patients that don't have access to insulin, which is a drug that is off patent and should be available to everyone.
So it's an. And neglected disease doesn't necessarily equal a neglected patient cohort.
And not all of the questions have to be answered with novo discovery.
A lot of the questions can be answered with making drugs available to certain patient cohorts.
And this is not my area of expertise, and I'm very, very grateful to be working with the FBI on this problem,
because they have the kind of IP lawyers, access specialists that are looking into these questions.
The one unique thing that the moonshot, the kind of the research effort I'm involved in,
can contribute to this theoretical question of how do we make drugs?
The sensible is that it is an open access effort.
Right. So that brings me to my next question. So I still haven't quite got sober yet, which is about you talked about open science, open access.
What do you mean by that?
And what precedents have there been within Oxford for setting up conditions under which that kind of open approach can take place?
So I am talking about SGC, just. Yes, I am.
Open drug discovery again. If you ask ten people would get ten, ten different opinions on what open drug discovery actually means.
And so being SGC and Oxford has that field.
I should have said the study consortium has been founded in 2004 and actually doesn't only only have an Oxford site.
It was a worldwide effort and it has a Canadian side.
And Edwards has been absolutely key to this setting up this effort.
It was very much his personal interest in looking into how can we generate.
Only tools that enable drug discovery in an open way across companies that are how can we kind of basically pool efforts and across pharmaceutical
companies so that if the idea is actually quite revolutionary and it's getting different pharmaceutical companies to pay into a covered pot,
they can nominate targets. And then there are different sites worldwide that bring different kinds of expertise.
And they will work on enabling these targets by developing tools and by tools, I mean generating structural data.
So this was the very first step. So that's why it's called Structural Dynamics Consortium.
So they would take some genomic information. This was specifically for human proteins.
So no viral proteins involved at that point. This is just specifically to target the human genome.
So they would go for a whole class of human proteins that at that point was under investigated.
So you wouldn't have this structure available and then kind of work on a whole class of proteins as a kind of wholesome approach.
Because what you also have to know is that if you saw one protein structure that doesn't yet gives you very much information,
you will want to know what the difference between this structure is and all the others to make sure
that you can develop a drug specific against the one portion of the class that you are interested in.
And there were actually several other grants that took this concept a step further that were also at the SGC,
where they didn't only look at the structure such, but also developed an acid for protein.
So this basically is is a biochemistry tool that you use to show how your protein works.
So you basically, if you, for example, as we will be talking about proteases later on,
these proteins that chop things up and keep other proteins or and and in.
And and material. And and these proteases and all the functions of these proteases you can assess in an essay and an assay,
we'll have a readout that you can measure at the end. So you would look at, say,
a little piece of protein and that and you will find some way of showing whether it's together or all cleaved into two pieces.
And that's a function of your protease.
And then if you add certain inhibitors that are supposed to inhibit your protease, you'll see that you protein even stays in one piece.
If you inhibitors working or it gets do two pieces give you inhibitor is not working.
So it's a tool to kind of find out which inhibitors or which drugs or which fragments may be having some biological effect on that protein or not.
So and this you don't develop for you one protein of interest,
but you develop a whole protein family to kind of make sure that you get a kind of good picture across.
And and that is really what the pharmaceutical companies are very interested and what
the unique thing about the SGC was that they predefined but this is pre competitive.
We can use this information and it can be used across different pharmaceutical companies and will make this open be available so that
anyone can use this information so you can order the constructs from the SGC and and the SGC even went one step further and said,
we're going to develop proteins.
So small molecules that are not drugs that part earlier than drugs, but they are things that you can use in cellular assays,
things that you can use in your enzyme assays to make sure that you can show activity against that specific protein,
but not all the other proteins of that company.
So that's and yes, you see has been very successful in exploring the epigenetic space, kind of different classes of proteins.
And that and based on these probes and structures that were developed through this set up,
there are a whole class of drugs that are now in the clinic and that that kind of bridge from original efforts that are open access.
So I suppose yes, the actual outcomes are important,
but the principle of that sharing of of data at an early stage in the drug discovery process is
one that clearly has been shown to be beneficial even even to the commercially oriented company.
There's one exception here. And what usually happens within this effort is that the compound,
so the SGC would partner with the company on the site and target a lot of the
medicinal chemistry efforts to actually making this probe was run within the company.
And and one of the probes that was active at the end would be published and accessible as an open access resource.
As part of the kind of interesting setup that a lot of the other compounds that were developed in this process might not necessarily be open.
So there was there was an agreement within the SGC that the company can use the tools that are open,
available to run their own discovery efforts if they choose to do so.
And that was was done for some some companies and some SGC partners.
And this is where the coordination is very different.
So we'll get that. So let's let's get on to get the answer to.
So when just first of all, where can you remember how you first heard about the pandemic in China and when you
started to realise that this was something that we might send your own message and this.
So I heard about. I think I first heard about the pandemic from the news, but I very clearly remember an evening in December.
When my husband walked in and he works for the diamond source, he also told us because he works for black schools and they had a student.
And they have an antibiotic program where they get exchange students from China
coming to visit the UK on regular and five and kind of two monthly times I think.
And the student had arrived in in the UK.
May actually have been John I can't remember the date but I,
this was kind of my first personal kind of interaction with the whole program
and this was the student had arrived and while the student was on the flight.
And China had started to lock down so that that student had left and came from an area where they work hundreds of cases.
And while this thing was on the flight, they had locked down back home.
And now the question was, what's going to happen to the students?
Because suddenly diamond, the accommodation that the accommodation that was booked for the students said, we can't have that student anymore.
And so within my my my partner's group, they were said to be this kind of uproar.
What are we going to do? Like, this person has to stay somewhere.
They can't stay in the accommodation because they're not going to have the student.
And we were kind of discussing back and forth. And then in the end, one of the one of the researchers and friends group said, like,
we've got an extra room in the house and my parents are happy to have her for that period of time.
And there were no tests available. There was no way to know whether the student.
But it basically ended up that the student that happened to find this about as a kind of self-contained
flat where they wouldn't be in touch with anyone else until they were able to fly back.
The student ended up staying and actually working on the kind of approaches of while they were visiting.
But that was my kind of very strong first for them and then.
Not a lot happened for a while. And and then we had two things pretty much happening at the same time.
One was I was starting to cough and that was in February.
So I have picked up COVID in February already.
So prior to lockdown or maybe early March and in hospital in one of my clinics,
I must've just gotten it and and started coughing and was aware that actually I actually may have picked this up,
even though officially we didn't have any COVID get in the country and at the same time friends group at diamond and was contacted by.
The Chinese research group that was working on the cells called the two main protein structure and
because thanks research group at diamond can very uniquely run very high throughput screens very fast.
And the group in China had solved the structure of the improprieties because they have been working on cells previously.
And that's a bit more about this mpro protease. And that the the protease is an interesting protein because the kind of research community,
similarly aspirin polymerase knows that it's a drug target that you can develop inhibitors against.
And so right at the start of the pandemic, there was obviously the question, how can we make a vaccine?
That was that was kind of one of the key questions and move very fast ahead on that.
And then if you think about, okay, what else can we use in our toolbox against COVID?
It's not only vaccines, it will be small molecule inhibitors as well, because there will always be limits to what we can do with vaccination.
And we will, especially at the start where we have got the vaccine, yet we hopefully should have something in hand.
And the obvious thing is repurposing efforts.
So using a drug that is already in the clinic and that also works against the new testings and unfortunately for COVID,
that was very, very unsuccessful.
And in a lot of ways, I mean, we've been able to identify immunosuppressive drugs that deal with kind of the legacies.
And I'm sure you'll be talking to a lot of people that have been involved with this kind
of game changing recovery trial that was also based on that on the small molecule front,
that was actually the direct acting antiviral from that was not very much that was able to be repurposed.
And what does the protease actually do and how does that help the virus things?
Okay, so so when the virus enters the cell, it enters through the spike protein and over to receptors ace2 and ramps to it gets kind of into the cell.
And as soon as it gets into the cell, it unpacks itself and comes into the cytoplasm.
And once it sits into the cytoplasm, it gets translated into not to long party proteins.
They are called open reading from one A and one B, and with this you can't really do very much.
But all like all the proteins that the virus needs to replicate and make more virus or contain them,
these kind of two very long bits of material and the protease kind of folds itself up and starts keeping itself out of this open reading frame,
but it also releases all the other proteins.
The main protease protease cleaves the party protein in 11 different state, and they make them different places.
And then there's another protease which is called the paper like protease, and that feeds in three different places.
And the main protease has some similarity to other viral proteases that we knew from experience can be targeted.
So we know from experience that HIV proteases have been targeted and this has an effect on viral load and HCV proteases have been targeted.
So hepatitis C virus parties have been targeted and that has no sex involvement.
So it was one of the obvious targets to go after. The other one with clinical validation.
So where we knew that if we inhibit that will have an impact on viral load is the polymerase.
It was those were the kind of two proteins where we kind of knew.
We have a chance. Basically, if we target those, we'll have a chance.
And one of the other obvious things was that these two proteins were taken and a lot of screens
were running against them to see whether some of the existing inhibitors find and inhibit things.
And unfortunately.
And we didn't really have any kind of hepatitis C protease inhibitors, for example, that work very well against the proteins and the polymerase.
That was a different game. There were.
And so Remdesivir, for example, was developed for and I think over there originally and it wasn't on the market yet.
It wasn't. But the whole development process had already been done.
And similarly, from olaparib, which was developed for RNA viruses that had been developed originally, I think it was for.
Venezuelan equine encephalitis was so easy.
And so a lot of the kind of development for that compound was also done.
And actually, the inhibitors that we have now Paxos it and which was developed by Pfizer and that
piggybacked on quite old drug discovery efforts that were discontinued previously.
So they used data that they had from source one and they use data and that effort even used data based on rhinoviruses.
So there's kind of quite a lot of background research on the proteases that kind of show that if you target this and that you can do it efficiently,
you may have a good chance to see something. The.
However, we didn't know until the phase two Phase two, three data from Pfizer actually came out that this was a target that was ten or 12 inches.
So it took another one and a half years to actually say, yes, this is a worthwhile target, to be honest.
Prior to that, we just were able to say it has worked on other viruses with some of the proteases,
but we weren't sure that it was going to work, but it wasn't a diversion.
So you would think that you'd be telling me how the Chinese have approached Frank analytically?
Yeah, yeah. I kind of ran away from that.
So the Chinese had contacted Diamond Lifestyles and specifically Frank's group and said, Look, we're going we've got the construct that was protease.
So the material that you need to run this this experiment, which is called a Fresnel screen.
And the aim of this experiment is to basically look at the protein and 3D shape and find the active site.
So the site where the protease cleaving and then you use small bits of drug, which are called fragments, to basically paint that active site.
So what you want to know is how would an inhibitor look like?
And that would fit very snugly into this active site.
And if you use existing drugs to do that, you've got a good chance that one part of the drug might make it,
but the other part hangs out on the other side. Or maybe it sits in a kind of weird position.
But if you use small particles of a compound,
then you have a better chance of mapping out the different positions very nicely and finding something that will bind with a very high affinity.
And also kind of you want to kind of find the basically.
And by using lots of small bits of drug and putting them into the crystal structure,
you may be able to kind of get a better idea of how this kind of active binding site is setup and what you may need to do to map it out properly.
So this experiment is called a fragment screen,
and that is exactly the kind of experiment that they run at the time like this for a whole lot of different human proteins, but also viral proteins.
And however, to run this experiment, you kind of need the protein construct that you then make your protein from,
and you would follow the protein the right way and have a crystal form to then be able to run this experiment under the x ray.
You. And the experiments with just the crystal have been run in China and the Chinese.
We contacted them and said, Look,
we can ship you all the constructs over and we can even ship you the protein over for you to run the fragments cream and the Cooper Diamond said,
Yes, we will drop everything and ship us the protein.
However, the Chinese group was hit by the local lockdown and they weren't able to actually ship anything because everything was just shut.
And so they just gave the diamond group the information.
And Martin Walters group of diamond expressed the protein very, very fast.
And the team at Diamond literally dropped everything and rammed this fragment screen as the absolute priority.
They generate a lot of different structures, and we're actually really lucky that the fragment screen ran so well.
And they've got a lot of different fragments and decided that this information has to go out
in the open as fast as possible and to enable drug discovery efforts to use that information.
And. At that point.
That was where the real difficulty started because the Diamond team had run this kind of fragment screen at very high throughput.
But what is not yet established is technology to get from all these different fragments to an active compound.
So the so called interlinked finding.
So you've got different hints. So you've got some idea of what might fit into that finding size.
But none of these hits independently will actually inhibit the protein.
We'll have to make sure that this kind of thing gets going together or joined up and make a compound that actually inhibits the protein,
survives of animal or human and and actually has an effect on the compound.
And that usually is a very, very long process of 5 to 10 years to kind of get to that point.
And what? And Frank and a couple of his collaborators that have been trying to kind of work on techniques to
address this particular problem previously have decided at that point is we actually are out of orbit.
We don't really know how to get from a segment to a compound,
but we can outsource or crowdsource this problem and basically ask a lot of medicinal chemists to contribute to this.
And the kind of key problem is that the moonshot at that point decided, okay, we're crowdsourcing this, we're doing something completely new.
Everything is going to be in the open. We're going to ask medicinal chemists all over the world to look at this information and tell us their ideas.
And what we will do is we will make sure that these compounds are actually ranked and made and tested.
So near London and at the Vital Institute and Israel said, if you give me the protein I can set up, and I say, they've got a high acid facility.
And Chris Schofield here in Oxford at the Chemistry Institute said the same.
They set up a different kind of breathalyser with two different acids, one then all funny, the posterior,
which is a newly found biotech company and said, look, guys, we can't run this all on Google sheets or Google Docs.
We'll need to kind of make a better plan. So within one and a half days, one of his programmers, Matt,
have set up a website that all the medicinal chemists could submit their ideas to and then.
Very early in the process. And medicinal chemists that work for AstraZeneca antibiotics previously called Ed Griffin,
now works for a small biotech as well and said, I can coordinate this efforts and kind of try and help to rank the ideas.
He came involved and then John Cordero, who's working as in this case D.C. and New York and he has a I technique or I'm actually.
He's running a machine learning modelling that predicts which compounds will fit very
well into the active binding site and have a high likelihood of being a good inhibitor.
And he uses a technique called FFP for these calculations, he says.
I'm going to do exactly that for the Moonshot.
These are super complicated mathematical modelling calculations that I don't completely understand.
But what I do know is that he built the biggest, the world's biggest supercomputer,
running these calculations for the moonshot and through a consortium that is called folding a
term which basically uses GPUs from home computers worldwide to kind of group them all together.
So that was that was kind of the best thing when they came up with these ideas and then said,
we're going to tweet about this and then we're going to find some money between Cycle Christian's to try to get these companies made.
And so they all kind of went to that research budget.
And so what they could redistribute and to making sexual compounds a little bit of money here and there.
And then the kind of crucial step was the Ukrainian company.
Joining the picture and saying we can actually synthesise these compounds for you at cost.
So they were the kind of crucial contributor, not only because they were actually making the compounds,
you could have outsourced to other compounds, but they've also picked up all the logistics.
So they sent out the compounds as soon as they were made to Diamond Light source
to run the code crystal structures and also coordination around the project.
And that was kind of the birth of the neutron. I think that was the eight months, 2020 where where this all happened.
And then a lot of the response to to all these tweets was overwhelming.
So we submitted to the website, and I think I was going to I was going to sort of bring that up because this I mean,
the scientific community does use Twitter quite a lot now. Can you hear me?
Yes, I've just started using a microphone.
But the this was really off the scale, wasn't it, the extent to which Twitter expanded the moonshot project?
Yes, it was. It was definitely a much bigger response than the original team had expected.
There were suddenly like that.
I remember at that time, and I only know that because I was actually doing the homeschooling, feeling really unwell with COVID at home at the time.
But basically Frank was on 3 to 4 logistical conversations every day trying to set up this operation.
They were overwhelmed with responses at the start and and trying to kind of get this effort
off the ground was there was something that they had that none of them had ever done before.
So it took quite a lot of coordination between all these different sites because
everyone was sitting at home and all these medicinal chemists that saw these tweets,
looked at the data and said, oh, yeah, I actually I can imagine doing this.
This would do something. And so, yeah, the response was overwhelming.
And, and the buy in from the scientific community was overwhelming.
I think it was a unique situation because this came exactly the week where everyone was locked down suddenly.
And so this is so we're still only in the end of March 2020.
Yes. Yes. This was so the tweet went out on the 18th of March.
And I think the lockdown on the 25th or 23rd, 23rd was yes, it was exactly that time.
And I'm actually uniquely because so this is this is where the kind of uniqueness
of the moonshot every single compound was online and visible at conception.
So everything was completely in the open.
Everyone could see the compound. And as soon as we had an end, as soon as it was made and we had an enzyme result available,
it was on the website and visible to everyone so anyone could trace the information and see what had happened,
whether their compound was being round to be made because we couldn't make all the submissions.
We ran the submissions first and then made the top ones that we both work, both because of budget constraints,
but also because we didn't have enough synthesis capacity even at a company like me to make actually synthesising those compounds.
And the other thing that happened is that.
A lot of employees of pharmaceutical companies that would usually not be able to contribute to anything outside the company was uniquely able to
contribute to this because there wouldn't be any patents on this chemical matter because everything was open and disclosed right at the start.
So that was something that was.
Unprecedented, I think. And the other thing that was unprecedented was the interest from pharmaceutical companies to contribute in-kind.
So for example, we had a whole team of medicinal chemists that came to the weekly meetings and were able from the company
to contribute a slice of their time to synthesise or to design compounds for the moonshot effort.
And that's in addition to the people that were sitting at home and just doing this for fun and.
And I think this the timing was was unique.
And also the way of doing it was unique and was very much kind of spurred by the pandemic because this
was something of interest to everyone and which which probably won't be repeated in this way ever again.
Or maybe it might be. Let's hope not, because let's hope we won't have the situation again where we'll all have to lockdown because of the pandemic.
So what you've described is like a kind of massive filter that's taking in an enormous amount of material at the top.
And what you want to get out at the bottom is a drug that can be used to both to prevent and to treat the virus.
Is that the idea? And sorry, another question at this point.
This is you mentioned that while all this was going on, you were homeschooling at home, but you were very much part of the moonshot project.
So what was your role? So I joined a little later and I wasn't involved at the right at the start, and I was actually at that time helping Nicole's.
It's my news of our just to get Oxford to set up a screening facility, and that was for repurposing compounds.
So I have a slightly different role and basically all my normal work which was on epigenetic inhibitors shut
down completely because then all all non-essential corporate work was deprioritized and didn't happen.
But I had worked on viruses before quite a lot and actually had grown viruses as well.
So I had the necessary expertise to set up help set up that part of the kind screening program.
And right at the start, the mutual obviously didn't have any compounds.
It takes time to make these compounds. So I wasn't involved with that part of the work.
I was trying to set up a screening facility with with Nicole and William James.
Obviously, that also didn't happen that fast because we had to kind of get some virus first, make sure the virus is growing.
And my my role in this kind of whole setup was very organisational.
So I looked through all the nominations for screening, ranked those for the process and, and then and ultimately able to send you the screening.
So it was a very, very different role. But as soon as mutual funds were available,
I was then able to help to coordinate all the cellular screening of the capacity that we had at Oxford was insufficient in any way.
So we felt like we had a massive buy in from anti-viral groups worldwide that said, yes, we can screen some compounds for you.
Like some of them were fairly high throughput because of the technologies they use them because of the access they use.
And some of them were very low throughput, so some of them screened maybe five or ten compounds, some of them screened hundreds.
And so it was very dependent on what was exactly used in that.
And that particular set up.
But then my role kind of evolved, and most of the work that I was doing, I was doing at night because during the day I was homeschooling.
And it wasn't directly linked to the moon shot. But at the time that the moon shot actually had some of the active compounds,
we had all setup running to contribute to the neutrons that kind of all came together.
So right at the start when everything was set up, I had a wolf, a commenting role,
and I was just very interested to see how everything was working out.
But my actual daytime job was very different and only and I would say probably early June.
That was when I when I started contributing to the job, because that was when they had active companies coming through.
Does that answer your question? Yes, it does. Yes. Yes. And and so how did it develop from from there?
How how what what what what have been the main outcomes of the project?
Okay. So this is now June 20, 21st.
It became clear and during that time that we were on to something.
So we at that point had several medicinal cannabis, hemp seeds, several series,
so different compounds that looked different that showed cellular activity.
And at that time, we had to decide which of those to take forward.
So we were trying to kind of screen as widely as possible across the series to make sure that we
had and that we chose the right one to take forward because of the kind of financial constraints,
we basically had to get our compounds a lot more potent.
At that point, they were potent,
but they weren't at a point where we would expect them to have a good antiviral effect once they are going to be put into human.
So we had to drive the potency down and at the same time, we also had to kind of figure out whether these were the kind of compounds that would.
Survive and and a human.
And for that, you do a range of tests and these tests are usually done at contract research organisations and they're very expensive.
So we had to start looking for money to pay for that simple grants.
And up to January 2021 and it was actually extremely difficult to come to find money to fund a novel drug discovery because we were still hoping.
To solve the problem completely with vaccines. And actually, we've done tremendously.
We're so lucky that we have done so tremendously well with the vaccines and.
And we were also still hoping to find some kind of repurposed drugs that so some kind
of existing drug that would get us around the fact of having to develop a new drug.
And it was clear at the time that there were a few companies working on this.
But what we didn't know was whether any of these new compounds would actually work and how quickly they would be available.
And the effort that Pfizer has put down is actually absolutely unprecedented.
And they invested a lot of money into it upfront with a very high risk to get to that.
So we were never in the position to match that. But. What wasn't clear is what would be coming afterwards.
And the other experience that we do have from anti-viral drugs is there will be resistance developing.
So we will always have new viral strains coming.
We'll always have to have not only one drug available, but several drugs available to be able to combat a new circulating strain.
And we can't predict very well what that is. That new strain is going to be.
We may have some idea,
but basically the best that we can do is have an arsenal available that targets different proteins and targets them in different ways.
So that's we knew that at that point, but we weren't actually able to move very far ahead without additional funding.
And so my main role in the setback in the coming months was actually trying to
look for funding and trying to write grants that would fund the next steps,
but also to ask for in-kind contributions.
And at that point, we were actually much more successful asking for in-kind contributions from other pharmaceutical companies,
then asking for funding. So a lot of our funding approaches were deemed as not in scope because up to
2021 novel drug discovery was not in scope for a lot of the grant applications.
It was only vaccine development, clinical trials and repurposed drugs.
That only changed in 2021, and that's when we started talking to the Wellcome that is now funding us.
And for this effort they started funding as of July 2021.
And for the making, the optimisation and preclinical stages.
What happened prior to that is that several pharmaceutical companies bought into the project and often alongside
internal efforts that they are pushing themselves and provided us with huge amounts of in-kind contribution.
And in all cases and contributions were mainly.
And Acme testing. And ACME testing is something that everyone who works on drug discovery bodes very well what it is.
But it's a it's a pretty theoretical concept for everyone else.
So basically, it's a range of lots of different tests.
How do you how do you spell it? It's an acronym, say BMB stands for absorption.
So how does the drug get into the body and distribution?
How does the drug behave when it gets into the body, or does it tend to go into kind of the fat tissue?
Does it tend to kind of stay in the blood volume then metabolism?
So basically what happens when the drug is the liver and which enzymes if the drug, how quickly does that happen?
Does it block enzymes and then elimination?
So basically, how quickly does it leave the body again?
And which transporters does it used to leave the body again?
So at a end. And all like there's one way to test it, which is to give it to someone and see what it does.
Obviously, you can't really do that with a new drugs because it may be toxic and they don't want to give it to someone at this point.
But what you can do is run a lot of kind of tests to see what each of these parameters may look like.
By the time you've actually put this into a human being and for example,
you may use some liver cells and put the compound onto the liver cells and see how long it survives when it gets chopped up straightaway.
Or you may add it to some transporters and see how quickly it gets transported in and out of the cell.
Or you may look at plasma protein binding.
So you will have some human serum and add the compound to it and then see how much of the compound gets bound to the serum and how much things free.
And all these are very important parameters to try to work out how whether you compound might be
something that may behave very well in humans or might be something that is actually complete and.
You can give it to a but it may not even be taken out.
And so this is and all these tests are very, very important, the correct discovery, but at the same time, very, very expensive to run.
And so we were very lucky because Novartis, the company basically as in-kind contribution,
gave a whole block set of the tests to the COVID moonshot as an important contribution and enabled us to run this these tests of that company.
Roughly how many compounds we are looking at at this stage. Hundreds.
Hundreds. I'm sad to say. The thing is, it's also it's not not that we make all the compounds upfront and say we are going to test movies.
What, it's a cycle. So you make the compound, you see, oh, this works really well, is really potent.
That actually it's cleared too quickly and it doesn't really behave that well
when you actually exposed to the liver and then the medicine covers the clever.
So if we change this little bit here on the compound, that may help us.
So you make that called politics to the game. I see it's not token.
So we have to try loads, different ones to get the potent one again.
And then you test the game and say, okay, so this time we came up with something that behaves well in the liver and is potent,
but actually it there may be something else wrong with this.
So and actually if not taken up into the body.
So it's it's an iterative cycle and you kind of narrow down and test different things.
And at the end, we tested probably around 600 or 700 compounds in different tests of different combinations.
Overall, we generated 2300.
We actually made 2300 compounds to get to the kind of three compounds that we are now evaluating
closer and that we still we're still not at the point where we can say this is our final compound,
but we can take it to. So if you said three, you've gone from hundreds to three.
Is that what you said at the three stage? And actually, this is what the Wellcome Trust is funding us to do,
is get from 3 to 1 compound and actually have have one compound available that we are planning to put into clinical trials next year.
So that's where we are currently at. We are running all the preclinical scale up,
which basically means making a whole lot of other compounds so that you can like at the end of the month to actually give it to patients.
And a whole lot of process chemistry is required for that because what you have to imagine is we made tiny,
tiny amounts for the use of this compound to look at cellular assays and all these tests.
But if you were to give it to a patient, we actually do quite a lot of it.
How much exactly is what we're trying to work out at the moment?
And this is this is called process chemistry. So that's that's part of what's happening right now.
And there's a whole lot of other process chemistry and you'll hear a lot more of that with the vaccine people is what
comes after your phase one to actually provide hundreds of thousands or ten of 400,000 people with these compounds.
So that's a whole different ballgame again. And that's where pharmaceutical industry is actually pretty good at.
So so do you have do you have a pharmaceutical industry partner who's taking all that on?
No. No, because we haven't got the patent. So it will be very difficult to make money from our.
We'll be more like a generic company.
Yeah. That would be interested in this kind of product.
So that's, that's very much what is happening in our strategic discussions at the moment with the eyes.
How can we come up with a set up that entices a generic partner to work with us on this?
Because it is quite unlikely that a pharmaceutical company will have enough interest in a compound
that doesn't come with the patents where you can't earn a lot of money off the compound.
So basically this this would be a cheap compounded generic from the start that is available to the masses.
So that's I mean, in a way, it's a unique selling point in terms of drug access.
But if you want to add a lot of money up a compound, it's not particularly attractive.
Mm hmm. Very interesting. So I've got so two questions of that.
So one is, first of all, what how do you envisage this company, if it works, if it passes all these tests?
How do you envisage it being used in the future?
Is it is it would you give it prophylactically or is it something you would give to people who have symptoms or how would it actually be used?
So if you think about like natural infection of courage,
what happens at the start is you get exposed to the virus and then you get a viral load increasing.
And then right that what happened right at the start is because we didn't have any natural immunity, we didn't have any vaccine responses,
and we did see the kind of innate, innate immune response kind of rising up and generating this kind of very acute picture.
And that is where a lot of the immunosuppressants worked kind of when you got into hospital and they keep dampening down that immune response.
What we are talking about is this kind of first increase in viral load.
So this is a drug that would have to be given very early after infection.
And it's similar to Paxton's actually exactly the same sex marriage.
You have to give it as early as possible.
It works best if you give it within the first five days and it will decrease your likelihood of developing a innate immune response towards the virus.
And that then brings you into hospital or if you die at the what is happening at the moment is that this picture is changing completely
anyway because we've got a lot of natural immunity that is developing with all the different variants that's coming through the population.
And a lot of people are not dying anymore, but still getting quite sick from the viral load.
So what we would envisage is to use this similarly to how we use a lot of flu or Tamiflu.
So right at the start, when, you know you have been exposed, you may have just had a positive test.
That's when you take the drug. And you would hope that that would ameliorate your symptoms.
But also, if you are at risk, patients that may not have an immune response yet was not eligible to the vaccine at that point.
Would. Lower your risk of hitting a hospitalisation point would lower your risk of death.
And in the kind of worst case scenario. Here again,
we're kind of moving into a bit of a difficult space because what we and the clinical trials and points that we are looking at currently still have
death and mortality and clinical trials are hospital admissions as the primary end point or even just a drop in the oxygen load or clots developing.
So everything that kind of comes in the later stages. We may have to look very different end points in one or two years time to come where we look at
symptom duration or just lowering of viral load as a kind of public health intervention in a way.
And so this is this is a very rapidly changing field.
And the part of that that we can't predict is what is going to happen if there's
a virus coming along that evades immunity much more than public health,
then, for example, we still expect the protease inhibitors to work quite well across the different coronavirus strains.
So that's something that we know from. And part of genetic sequencing is that the protease is relatively constant.
It's not quite as close to the race, but it's more conserved than, for example, spike protein.
So it's a good likelihood that the protease inhibitors will play a role for new strains developing and that escape the immune response.
But it's a very changing and unclear picture, so it's a good question.
My ensemble will look probably very different to what my object would look like in three months.
But you have at least you have the funding to take it forward. So that's really good.
So looking at looking at this that the the the amazing process that you've all gone through,
do you see this as a model for future drug discovery or do you think this was a one off?
I think that's how it went and the speed it went.
That was probably a one off. However, I think we can learn.
We can take very important bits and pieces from it and apply them to different diseases and also to similar diseases, but for different compounds.
And part of that is actually what we're doing right now is setting up a new consortium.
We got funded by the NIH, which was funded by The Age,
to set up one of their avid drug discovery units, which is basically a virtual drug discovery unit.
It's very well funded with $68 million across five years.
And this is funding for pandemic preparedness.
So basically generates so basically repeating what we've done for the moonshot, but all different kinds of viruses that may have pandemic potential.
And we will reuse a lot of the kind of open access ideas and pro-competitive ideas for this new consortium.
And that's that's a very interesting project for us because we can actually implement a lot
of the learnings that we have from the moving into that similar drug discovery effort.
I think there are lots of other diseases that.
This could be relevant or parts of this could be relevant too. So I'm thinking.
Amal So anti-microbial resistance would be one of the obvious fields where a lot of competitive science would be extremely
worthwhile to the field and but also a lot of the kind of thoughts that we have on the kind of potential return on investment.
Once you develop the drug, it is crucial to advance the field as well and potentially rare diseases.
So, yes, there are things that we can learn. I don't think the exact setup could be repeated.
That was probably something that was very new to the pandemic with the acceleration, even though we were much slower than, for example,
Pfizer that was doing a very similar drug, although very different mechanism,
like if they want to give it to that, we are having convey the point that they're having.
So they looked at differences and. We couldn't have done it at that time scale.
But and even our timescale is extremely accelerated in comparison to what might be possible in a non-pandemic setup.
And also, I think the kind of demands and time contribution would be very difficult to generate in the future for other kinds of business.
But I think a lot of the ideas should be taken forward in different avenues.
Well, I mean. Oh, we've only got 3 minutes left.
So which I have to pick a question to ask and. Well, last night, I guess the usual.
Final question. So has the.
Has your experience of working through this on this project through the pandemic changed your attitude or your approach to your work?
And what would you like to change in the future?
It has been absolutely crazy the last two years, both personally trying to kind of just get everything organised,
like having the kids during the day, which you couldn't send back to school because we had COVID in the house.
That would have been a key marker. And actually at some point Frank was admitted to hospital with COVID while the child was running.
So I'm like both on it. I would like to to repeat the personal experience of the pure workload, but also the feel of urgency around work.
So I'm actually looking forward to using all the bad eggs, the professional learnings that I had,
and it has been an incredibly incredible learning experience and just thinking about forwards.
Into into the next phase and using that to basically deliver compounds and and and knowledge for the common good.
So that's that's that's something that I feel very passionate about.
And I think I got even more passionate about it in the last two years.
Seeing like how there is still such a divide between access to treatment and drugs here in the U.S. and kind of in the developed countries.
And then compared to what what I can see and that starts with testing, actually, it's not actually just compounds with drugs.
It's it's access to health care. So it's something that I feel even more passionate about than I felt beforehand.
So that's something that is definitely more pronounced.
What was absolutely unique and what I would like to carry forward as well is this feeling of We can do this together.
And and that is something that I now also find very strongly in the pandemic preparedness.
Feel that everything is working towards now is that we will need to keep this sense of togetherness.
Some call to arms to be prepared for the next pandemic because the likelihood of that is unfortunately not that low.
So that's that's something that I would like to maintain.
Excellent. Thank you very much. Oh, I've lost my cursor again.
Come on. Where is it? Thirties.