Okay. Could you just start by saying your name and what your position here is at Oxford at the moment?
Yep. So my name is Henry Chan and I'm an.
There we are. Now, I think I need you to go back to just telling me what you told me about the scent of doctoral training and your supervision.
Yes. So I'm a student at the Synthesis for Biology and Medicine Centre for Doctoral Training.
This is a program here at the Department of Chemistry at the University of Oxford.
And and, yeah, I'm jointly supervised by Professor Fernanda.
Do I tell you on the computational organic chemistry? And Professor Chris Schofield, working more on the biological and organic chemistry thoughts.
And tell me how you first got interested in chemistry when you were at school? Yes, I grew up in Hong Kong and did my high school there.
And yeah, I've always enjoyed doing experiments and chemistry lessons and just seeing how things work in real life.
And I've always been fascinated and sort of fascinated by the different applications of chemistry from textiles,
plastics to the medicines that cure diseases.
And yeah, and I guess as if every young kid back when I was in kindergarten, I experienced the the first source outbreak in 2003.
And that sort of provided me with some motivation to use chemical knowledge
to solve medicinal problems and to help tackle diseases in regard to and to.
Yeah. Yeah. And how did you come to be doing your dphil here in Oxford?
Yeah. So I did my undergraduate. I had Oxford as well.
And, you know, just really enjoyed doing organic chemistry while I was an undergraduate and and I did one year and the final year and can project
with Professor Chris Schofield during which I studied the beta lactam cases which were important enzymes in antibiotic resistance.
And yeah, since then I've really enjoyed the research and.
And George working in the interface between chemistry and biology.
Hmm. Mm hmm. Well, coming from East Asia, as you do, presumably you have pretty a life to what was going on in Wuhan when it first happened.
What were you hearing about from family and friends? Yes, I remember the news probably appeared when I was about two,
and so I was having my Christmas holiday in Hong Kong and that was around the time when I flew back to the UK.
But initially I thought it might be just similar to what we experienced many years ago,
that there will be a short and maybe just local outbreak of coronavirus.
But that turned out to be wrong.
And yeah, and the virus spread to different parts of the world with it was much more contagious and much later than we would have thought.
And yeah, I remember in February 2020, I was still able to go to London for a computational chemistry workshop with some colleagues.
But then and then we were a little bit worried when we were on the flights, but then yes, still managed to travel, but eventually in March,
then things worsened quite quickly and and we had to start working from home and went into the first national lockdown.
Mm hmm. And what stage were you at in your Ph.D. at that point where you're still doing your first year?
Or have you chosen your project to do it for the final part of your dphil?
Yes, I was beginning my first of the third Substantial and Dphil project.
So back then I was doing some computational modelling on metabolic directions and also and on a cancer related protein called citrate dehydrogenase.
And so when the the group the way to group, you know, Fernanda and her colleagues started to meet regularly to talk about working on on COVID.
Did you did you become involved in that straightaway? Yeah.
So, yeah, I was so introduced to this project by both Fernando and Chris and they asked me whether I would be interested in doing some computational
modelling to look at the activity mechanisms and also the binding of inhibitors to the SARS-CoV-2 corona virus main protease.
So mpro and yeah, I've been yeah, of course I'm just asked to take on this project.
So I understand that you and three other graduate students, two from here and one from another university, really quite took the lead in this project.
Tell me about how it developed and how that came about. Yes.
So I guess so as a computational chemist back then then was mostly working from
hype and and then also within the Schofield Group so also supervised by Chris.
And and there's also Teeka Kamala Dphil students are working here and just she came into the lab
to and did some and some work so developing assays and testing different inhibitors against them.
And and but the work also involved collaboration with the group of Professor Garrett Morris at the Department of Statistics here at the University
of Oxford and was yeah initially got into contact with Garrett through I think because I had some questions on using talking to so computational
methods to predict how inhibitors binds through the protein and those initial questions opened up that possibility of starting a collaboration
with him and also with his graduate students and Mark and and eventually that collaboration went further and also to the University of Bristol,
where we collaborated with the group of Professor Adrian Mulholland with a graduate student,
including back from her and also other other academics at Bristol, such as Sophia and Debbie.
And, and yeah. So the, the collaboration just got larger and larger as we, as we developed and did that.
I I'm just wondering if social media was involved in this.
Did you was was there a any kind of sort of call out on social media that let the community know that there was something going on,
that that was that you were open to collaboration? I think it was mostly maybe collaboration and knowledge, but direct to the supervisors.
Yeah. Mm hmm. And so how did this you I think when we I was talking to Fernanda earlier, she talked about the regular Wednesday meeting.
Was that an unusual way of working in science and what what happened at those meetings?
Yeah, I think so. So, yeah,
I think we started off having a6pm Wednesday and meetings where we discuss and exchange ideas and or say computational and experimental results
on the SARS-CoV-2 improved and during which we sort of because we all came from different backgrounds and had different areas of expertise.
So it was we exchange ideas on the methods that we're more familiar with and
also and the results and and that sort of pushed the collaboration forward.
And through that exchange of ideas, we are then able to develop new ideas, design new inhibiteurs that eventually were tested in the lab.
But let's go into that a little bit more. So tell me, first of all, what was your your personal role?
What were you what was the challenge that you with the you set yourself to to solve in this as part of this project?
Yes. So on empathy. Yeah. I've been involved in sort of two smaller projects, one at a time and it's fun.
Yeah. So, so the first one is more about the fundamental question of how it works.
And so I've been modelling the and the main protease complex with its native substrates and modelled us short
poets and then fruit and molecular dynamics simulations and analyse how the protein interacted with those.
Interact with these substrate peptides and see what are the key interactions that we might be able to exploit and design inhibitors.
And the second branch of the project is to look at how inhibitors bind and how to design better inhibitors.
And these inhibitor protease is a big molecule. The inhibitors, they're much smaller.
Is that is that right? Yeah, I just said that just looking to dock in a particular point on the bigger protein.
Yes. So there's inhibitor molecules are more drug like and because what's their interest and helping with the drug repurposing approach.
And and here the experimental colleagues have also tested a range of and different compounds that are already drugs and lots of yeah.
New drugs and and you're just blocking those and seeing how they might bonds to improve and that's that's all done computationally yeah
computational computationally even but also and complemented by different techniques here and then by experiments and also sometimes if,
if we're lucky, a crystal structure will not get into that as well.
And and roughly how many compounds be happy did you look at in the course of the process?
I think there are quite a lot. So hundreds and hundreds.
But don't yeah. We switch our focus to maybe just around ten or so to so do you do.
Sorry to interrupt, but do you mean do you do the one by one or does the computational approach allow
you to screen a whole lot at the same time and then see which ones work best?
Yeah. And we're able to screen them a large batch initially, but then yeah, I guess eventually as the project developed,
a small experimental data came in and we're able to turn our focus to a smaller range of compounds,
so maybe around ten compounds to, to look at to more specifically.
And how well did they seem to be working that's inhibiting the protease?
Yes. So I think there's though, maybe just a feeling like for me that in terms of inhibition.
Affinity. Yeah. So but yeah.
Can you explain that in more everyday life?
Yes, I guess they're able to to binds through the protein and actually because MPRO consists of a nuclear like system residues.
So that's involves a sulphur that's and that attacks the substrates and helps catalyse the whole hydrolysis reaction of the amide bond.
So those inhibitors are able to to target sort nuclear for the existing residue and and
modify it and to form a confidence complex that's unable to perform its native function.
So is it so does that block it completely? I think well it's like it's dependent on concentration, right.
It's a for goes through and the like. Yeah. Under a process of optimisation.
Yes. Yes. And that then so the idea would be then to to take that work further and develop those those compounds,
those blocking compounds to see whether any of them might have promise as as antivirals.
Yes, hopefully. Yeah. And so that rather not your, your, for your dphil program, um, well into a different course let's say.
But I guess in the end it doesn't as long as it is worked as well as so I mean, did you,
have you had to read to rewrite the title of your of your thesis or will it all be included in, in your original program?
Yeah, I, I had to revise and sort of switch my focus from my initial projects to this new project of modelling the SARS-CoV-2 proteases and.
But, um, I think that's yeah, I would have to take on this project.
Absolutely. Yes. It's clearly a very fashionable no, that's the wrong way of putting it.
Important area, area to be in.
Um, and I mean, it sounds terrible in a way,
but in some ways the fact that there has been this terrible thing that's affected the world has presented you with an opportunity
to to really break new ground in a way that might not be open to a lot of people at your early stage in your career.
Yeah, I think.
Is the the free the free exchange of ideas and knowledge and expertise that really helps develop this project and help us achieve some results,
both computationally and in the lab.
So yeah, without you both, there's this, I guess,
Norm of working for soon and having some meetings and being open to online collaborations that
might not have started and maybe I wouldn't have learned that much from my collaborators.
So another thing I've heard of, I just put this in here is the COVID Moonshot Project.
Is that something you've been involved with at all or is that completely separate?
Not really, no. I don't even we need to talk anymore about that.
Yeah, I've just been doing my research online and finding these things slightly overlapping, but not not quite.
Some of the collaborators I think have been available for that. So, yes.
So how again, how was did you find it personally having to suddenly work remotely and lose the kind
of interaction which is the student you would you would normally expect a lot of,
you know, close interaction with colleagues and friends. Yeah. That's a that's.
Dphil student Yeah.
Initially, as I took on this new project, there were still lots of things to learn and a lot of papers to read and a lot of literature to absorb.
So and yet, back at the very beginning of the first lockdown and remember, like working quite hard, just trying to get resources as soon as possible.
And that probably helps. And yeah, it keeps on kept on motivating myself to, to progress on this project.
But I think eventually a start as the lockdown prolonged,
I just started feeling the impact of working alone and being maybe a bit lonely and yet lacking the the support
and the conversation you would usually get when you're working in an office with your fellow colleagues.
So, and yeah, it got a bit tough later and there are many ups and downs during this journey.
But, you know, thanks to the support of the collaborators and my supervisors and friends and family support
to overcome these challenges and continue making progress and continue with my work.
Were you living in college or in a in a in a rented room somewhere?
Yes. So initially was working from home, but then I moved into my college career and from there.
And of course, your family. Your family still in Hong Kong, so. Yes, I was with my family.
And being far away must have been very easy. It was difficult and.
Yeah, yeah.
Yeah. So what's your main focus at the moment?
How are you trying to take this work forward? Yeah, so I'm trying to finish up.
Well, there remain many unanswered questions and about improve and uh, because uh, there,
there have been experimental data on how I'm actually and the activity of empathy towards these 11 different and native subjects.
So I've been trying to understand by a computational chemistry why this difference and its the way it is.
Um, but also um, extending my project a little bit more and I've been working on the computational modelling of the papain like protease,
also known as property, and that's also an important and a protease enzyme in the SARS-CoV-2 Corona virus.
And it helps the virus evade the human immune response.
And, and yeah, so working very closely with some experimental colleagues and on that and, but, and me focusing on the, um, the computational side.
Mm hmm. Mm hmm. So that that would be an alternative route to blocking the.
The virus. Um, as you said, so not so much the replication, but the evading of the.
Of the immune system. Yes, definitely. Mm hmm. Mm hmm.
Very interesting. And. Yes.
I think I think you did answer this really that it was the same question that I put to to Fernando,
whether you felt that having an important job to do helped to support your own wellbeing through the through the pandemic.
Yeah, I think maybe one important, important lesson I learned from working from home is be understanding and caring towards each other because
like I'm sure the lockdowns and like these few years of living under COVID have been really difficult.
And sometimes we have and the circumstances might be different and circumstances about family,
about friends and different worries about the world and the pandemic and just
trying to be and to be caring and reaching out to help others is really important.
Mm hmm. And that's that's interesting because I think I mean, a lot of people find that the early academic careers are pretty tough and competitive.
And actually, you're not the first person who I've interviewed who said that it was such a revelation
when working with the COVID project to to be working in a much more collaborative way.
And that the the competitive side of it was kind of dialled down and the cooperation was dialled up.
And I wonder if that's a lesson for how to manage science better in the future.
Yeah, I think we definitely being open to collaboration to the free exchange of information and expertise.
And though science is a competitive field, but at the same time,
after we have a common goal of making lives better for everyone in the world and solving real, real world problems,
like no matter whether it's the energy challenge, food challenges, or in this case, the current coronavirus pandemic,
and just working together and being able to share that information, that expertise is really important.
Mm hmm. So I must excuse me. I'm assuming you're going to want to stay in this field for the future.
You sound very enthusiastic. Yeah, probably, if it's hard to predict, I suppose, but, yeah, I would like to continue using my chemical knowledge and.
And maybe experience and or computational chemistry to continue working on topics of medicinal relevance and.
And sort of chemistry at the interface of biology and medicine.
Mm hmm. Well, thank you very much for doing.