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BlueSci Podcast

Released 20th April, 2020


Ruby Coates & Simone Eizagirre 0:05

Welcome to the BlueSci Podcast, brought to you by Cambridge University Science Magazine. I'm Ruby. And I'm Simone. Every two weeks we speak to local researchers, university staff and students and anyone who works in science to learn about their research and activities. hear about the work that they do and uncover what goes on behind the scenes. If you want to get in touch with a question suggestion or just want to be featured on the podcast, just drop us a tweet. Our handle is @BlueSciPod, and you can also email us at [radio@bluesci.co.uk].

Simone Eizagirre 0:50

Hello, dear listeners! So this week, we're speaking to Stephen Baker, who's a professor of molecular microbiology at the University of Cambridge and his lab has been one of the first academic labs converted into a diagnostic labs diagnostic lab, which is now carrying out validated rapid testing of staff at Cambridge is Addenbrooke's Hospital. So he's here to tell us all about testing and you know, what we can expect about testing for COVID-19; what kind of tests there are, and kind of - clarify any questions that we might have about that. So stay tuned to find out more. *Transition music*

Ruby Coates 1:28

Today we're talking to Professor Stephen Baker, and he's a professor of molecular microbiology. And he was previously located at the Wellcome Africa Asia programme in Vietnam for 11 years, but now he's in [the University of] Cambridge. And his research mostly focuses on norovirus, shigella and salmonella. But his lab was actually one of the first academic labs converted into a diagnostic lab, and it's now carrying out validated rapid testing of staff at Cambridge is Addenbrooke's Hospital. And it was actually set up and running in under two weeks! So it's quite an amazing effort. So uh, welcome! Would you be able to tell us a little bit about your work and your expertise in this area and in the area of infectious diseases in general?

Professor Stephen Baker 2:14

Yeah. So, um, so I got interested in, in bacteria, actually. So I always wanted to do human genetics, and ended up in a kind of strange, slightly strange circumstances thinking I was applying for a job in human genetics - and ended up getting a job sequencing bacteria, which then turned out to be a mistake, which - which was good, because I got even more interested in bacteria! So actually, my first honest omission is that I have no official training in microbiology whatsoever. So I didn't study microbiology at university it was actually later that I got interested in bacteria, and then did a PhD in London working on salmonella and then moved to the Sanger Institute as a postdoc and got interested in genetic variation and sequencing. But also then I realised there were limitations with understanding how infectious diseases work if you're not working in places where there are a lot. So in 2007, I took a job as a postdoc, and at the Wellcome [Trust] unit in Ho Chi Minh City. And I was there for almost 12 years. And I returned as a researcher here at Cambridge in the summer of last year, to set up a lab actually looking at how we can better understand genetic and antigenic variation in gramme negative bacteria to develop more kind of strategic approaches to how we kill them and prevent them with immunisation. And then, and then COVID came on.

Simone Eizagirre 3:45

And how was it that your lab was one of the ones that was chosen to set up this diagnostic response?

Professor Stephen Baker 3:51

We weren't chosen - we just did it. So I mean, I have I have some experience in this, so having, you know, worked in an infectious disease hospital before in Vietnam. We have done a bit of viral work in the past. And also, I have some background in trying to find viruses in complex biological samples from stuff that we've done in the past looking at actually, ironically, zoonotic transfer of viral pathogens from animals to humans. So we have some experience of this. And then when this [COVID-19] came along, we realised that probably this was going to be an issue: that there was probably not going to be enough capacity to do more testing. So we, we went over to the to the microbiology public health laboratory at Addenbrooke's Hospital, asked them what they were doing, they gave us some initial primers and probes and some positive material. And then we got going and set the machine up here to basically run those PCRs and then over a period of two weeks, came up with a mechanism of then how we deactivate the virus in swabs, and then also validated the approach on known positive patients. And then we're ready to offer it to the hospital.

Ruby Coates 4:59

So all set up really, really quickly! And the diagnostic test and that set up the PCR diagnostic test, would you be able to just quickly describe how that would work to our non-biological listeners?

Professor Stephen Baker 5:13

Yeah, so actually, we didn't, I mean, the truth is, we didn't really do anything that that isn't already known. So I haven't done anything - that's unfortunate, I haven't done anything that's going to win me the Nobel Prize. *Laughter* So we took existing methods, and so we realised that one of the one of the limitations with the approaches that was going on nationally is that the swabs when they're taken, go into something called a viral transport media.

Viral transport media is great for viruses because it keeps them alive and kills other things. And that's why it's always been done traditionally, because it means that you can do other things [other tests or research] with those samples because you may not want to kill the virus. The issue with something like this is because it's so transmissible and we know actually, you know, it's got a reasonable mortality rate, and that it's dangerous. So therefore, you have to those process those samples in a containment level three laboratory. In the UK we have four containment levels in laboratories - one being the lowest and four being the highest. And this is the three. And it has to be processed in a in a cabinet, which means that you're not in contact with the airflow, so that means that you can't contaminate yourself. So that creates an issue with respect to having access to those kind of facilities. It also creates a bottleneck because you have to follow certain procedures in those laboratories and not everybody's trained. There's a limitation on space and capacity and reagents and what you can do in those things.

So what we did to offer it as a test to the hospital, was take a homemade buffer, which is published, which we then put into tubes, which we then tested to make sure that they deactivated the virus. So it kills the virus as soon as the swab goes into it. And then that allows us really quick processing time because we can just process it and our normal containment level two laboratory. So that really, really speeds up the process.

And so then what happens is, once we've got those swabs, they're in that buffer, the virus is theoretically dead, but to make sure that it's dead, and to make sure that people are safe, we still process them in a cabinet so they're away from the airflow. And then we add alcohol to them to make sure that everything is dead. And then we put them through a chemical process, which removes the proteins and all the things and bits and pieces that we don't want. And then at the end, we wash it out and we dilute in a very small volume of water, which contains the nucleic acid. So nucleic acid is the genetic information that we have in all of our cells, and in bacteria and viruses and everything and that gets washed through and ends up in a very small amount. Within that there will be lots of genetic information, including that from the virus if it's in there. What we then do is mix that very small amount of that material with some enzymes in a different lab, and those enzymes then essentially photocopy the DNA that's in there, including the bit that we're interested in. And we have a particular set of smaller bits of nucleic acid, which we put in that mixture. And when we detect enough of the virus that we're interested in, then we get a light on our machine and the actual piece of DNA, and then fluorescence and that tells us we have a positive result. So the process is taking the swab, extracting the genetic information, and then essentially photocopying that genetic information with something with a "light on" if you like, and then if we detect the light, it tells us that the sample is positive. And in that we have a lot of positive controls and negative controls to make sure that our reaction works appropriately. And to make sure that actually we haven't contaminated anything - because it's very prone to us mixing things up or contaminating our reagents, which means then we would get a whole lot of false positive results which are results that are positive but not truly positive.

Simone Eizagirre 9:01

And how long does that then take from the moment that you're able to take a swab and then go through all these processes with your new -

Professor Stephen Baker 9:09

So it's actually relatively quick. So the limitation is people, and how much they want to be in after tea-time. But we theoretically, we can do it in four hours. So we can do in the time, the time that we received the swab to actually reporting the result, we can do that within four hours. Realistically, it's more like 24 hours because often we receive the swabs at the end of the day, and then we leave them overnight and then we process them in one day. We do the extraction in the morning report back in the afternoon. We can speed that up, but then it's dependent on people. But theoretically, four hours.

Ruby Coates 9:42

Wow, that is pretty quick. So most of the samples that you you're processing, am I right in thinking they're swapped from people who are working Addenbrooke's [Hospital] at the moment? Is that correct?

Professor Stephen Baker 9:53

Yeah. Yeah, there's issues there in the way that we - how we do that. So this has been another kind of slight complication. So we're not a registered diagnostic laboratory, we're a research laboratory. So we come and go, sampling anybody and reporting back results. What we do is essentially, we've offered it to the hospital as a kind of service. I wouldn't say so much as a research project, but more as more as a kind of, you know, the capacity for screening staff that takes it away from the conventional diagnostic laboratory, the diagnostic laboratory know what they're doing, and the doctors there, check the results. But we're doing it independently of them. And there is a disclaimer knowing that this is done in a non-certified laboratory, but we do everything according to the specifications that they're done anywhere else. We just don't have a certified status of diagnostic laboratory.

Simone Eizagirre 10:42

Okay. Maybe perhaps one of the issues with having this kind of testing being rolled out to different places, that there is that barrier due to the regulation, or capacity?

Professor Stephen Baker 10:51

Yes, yeah, sure, well, capacity is one thing, but also then having that you know, you can't have any laboratory setting up in any way and just doing testing and reporting about results. So there has to be some degree of certification to ensure that the standards are maintained. And our standards are good. I mean, we don't have any problems with standards, but we're not a diagnostic laboratory. So as long as people, you know, the swabs are taken, then they realise that it's being done here in an independent laboratory. And there are limits potential limitations associated with that, you know, that's okay. But we do try and maintain a good standard anywhere to ensure that we're reporting the right.

Ruby Coates 11:26

Yeah. Do you think that it could be possible that other labs could follow suit and offer some similar services and equally, and so would you encourage that seeing is, like you said, one of the bottlenecks has been working with a virus having to have a cat three lab, but now because the protocols can be changed working in the cat t lab, and there are lots and lots and lots of cat two labs. Do you think it could be possible that this sort of type of testing could be rolled out throughout their labs there in Cambridge, and in the UK?

Professor Stephen Baker 11:54

Yeah, sure. So as of this morning, the process that we've been through is in now public. So we wrote up a report that it's available on BioArXiV. So it's in the public domain. And there's lots of other people, I'm sure, that are doing similar things, as isn't the only mechanism to do this. But other people can do the same. And I would recommend that other people do it, there is lots of talk about building up capacity for testing for COVID. And then you know there's these big testing facilities, which is great. And I think they're a part of it. But also just having that smaller scale, perhaps interaction with the local hospital and providing results in a more kind of, you know, rapid turnaround time, and perhaps even having that more personal interaction between the university and the hospital, for morale and other things, has also been good. So I think there are things that you can measure and perhaps things you can't measure that make it worthwhile, and I would recommend that other research groups have the facilities to do something similar.

Ruby Coates 12:53

So speaking more sort of, broadly, what we're talking about at the moment is is PCR testing. There is talk as well about antibody testing and how this is slightly more of a less well-defined area. And as much as we're not even sure if there was any sort of concrete evidence as to what what antibody responses are raised, and if we can even measure it. Do you have any thoughts on that? Or, or is it possible to be rolled out?

Professor Stephen Baker 13:21

Yeah. So that's something that we've also started working on... not that I want to be known as the kind of COVID diagnostic king singularly. *laughter* So yeah. As we go through this process of screening people that are actively infected with the virus, so that's really key for knowing or who's got it, we, you know, either, from a diagnostics point of view with people in the community with it, that's important, but you can understand why it's important for health care, people and other key workers, so we don't want doctors and nurses on the wards with it affecting other people potentially. But also if they are ill, then we want to make sure that they're diagnosed with the right, with the right things. And also, if they're at home with other symptoms related to the disease, but a negative, then theoretically, they're fit to return to work, or if they're isolated because household members, so that's important.

But then as we then start to come out of lockdown, and people start to emerge from this, then there is going to be a requirement for knowing who has antibody. So there's two procedures. Really one would be an antibody test that allows us to detect whether somebody has has very recently or actually has the infection now, that would be a short term antibody test, and also then there's benefit of having a longer term antibody test. So that would be a different type of antibody. That would tell us whether somebody has had the infection and potentially has some degree of immunity to it. Now, there are tests that are being developed and there are some tests that are available. The problem antibody tests is they don't have the same degree of sensitivity or specificity as a PCR-based test. So if you amplify a piece of the viral nucleic acid in someone's nose, you're pretty sure they're infected with it. If you have an antibody response against it, that's not a guarantee that you're you are infected with or have been infected with it. And likewise, if you don't have an antibody response, that's not a guarantee that you haven't been expected to it. And also, if you do have an antibody response, we're not quite sure probably what that means yet and how that correlates with you having any degree of immunity.

So there are there are lots of things that we need to do. I think having an antibody test is going to be really important for getting everybody back to work, and also how we then start moving people around again. So I think knowing that you've been infected with it, and you're potentially safe from being affected with again, if that's the case, is going to be really key. And I think there's lots of people they're going to be working on these things as well to make sure that we have lots of different approaches. Hopefully they will all kind of work in unison with one another, to make sure that actually we can detect actually who's protected, who's not protected, and also, who will need immunising and who won't need immunising, potentially, when we have a vaccine.

Simone Eizagirre 16:12

And how does that work in terms of being able to validate those tests? Because if it is so ambiguous that, okay, you might have these antibodies or like you might have this response, but doesn't necessarily mean you've had the disease and vice versa, then how does that make it in terms of actually developing this kind of test?

Professor Stephen Baker 16:29

Well, I mean, at the moment, it doesn't. But the - the long term view would be that you have a an antibody titre of X, and we know what an antibody titre of X means, with respect to then having additional downstream assays of understanding what that antibody titre relates to having some functionality. And what I mean by that is what that antibody does, does that antibody concentration have the capacity to neutralise the virus? Does it have the ability to block the virus having activity? That then is a downstream set of experiments, and quite a long period of work to understand them what that antibody means. And then when you have an antibody titre of X and what that corresponds with, with how that antibody may or may not work.

Simone Eizagirre 17:13

So I guess in that - to make that kind of possible, do you think that then the people that have been infected, that we know have had the disease, will they be key to the study then ?

Professor Stephen Baker 17:26

Yeah, so I mean, so yeah, getting a cohort of people that have had the infection knowing they had the infection and being diagnosed with it, using a PCR test. So detecting the virus to know they've had it, preferentially been symptomatic, initially to know that they've actually been infected with it and got some response to it, would be useful. But then obviously, everybody at some point, those that have been infected with it perhaps and not been not had symptoms, or had mild symptoms, and then looking at the whole spectrum of cases, looking at their antibody responses. And then how that then works to understand what it means, and whether you have to have an infection and the illness to actually generate a protective antibody response. We don't do any of these things really as yet.

Ruby Coates 18:07

So, obviously, the antibodies for our non-biology listeners, is really, really important for sort of - your way for your body to fight off the virus, but also remember it and be able to fight it off again. And yeah, like he [Professor Barker] said, that's probably why that is going to be the main thing that's going to get us out of this situation. And sadly, that takes time to understand, the complex immunology of all of these things. So it's amazing how much work has been going on already about it. And there's a huge amount of COVID-related research going on right now. And sadly along with it, loads of rumours, myths, weird bizarre stories. You know, there's been a strange things been going on about something about 5G and people saying stuff about the TB vaccine and all these types of things. Is there any sort of source of information that you'd recommend for people to sort of stay informed without kind of falling into, you know, going astray? And sort of actually, you know, misinformation is is extremely dangerous in itself. Is there any sort of source of information you'd recommend for people to learn more about it?

Professor Stephen Baker 19:18

We live in a, we live in an era of fake news, right? So there's a lot of nonsense that's published and everything, it appears that you know, everybody, you know, one of the... Social media has had a massive impact on us on the way we distribute information now, which is clearly good. The downside of that is that everybody has an opinion and everybody's an expert on everything. So actually, scientists are generally honest in their approach, that they're never truly sure about anything. Science works with a degree of, of cautiousness, because we're never quite sure on what that means. So, when you speak to scientists to give you an answer, they probably never quite give you a clear answer because scientists are never definite about anything, because that's just the way science works.

So, I think yeah, I think what can people do? I think that when people read things, looking at the sources: where that's come from looking at, you know, chasing back the original information. So often, there will be a particular article about something that somebody has made a news report about, or come up with their Twitter opinion that suddenly goes viral, I would always suggest that people look back to the original piece of information that that's been, that's come from, and then for them to make their own decision. I realised that not everybody's a scientist, but people hopefully will have some degree of common sense, to work out what's feasible and what's not feasible. And I think that by looking and trying to decipher that information, and I think science can help to by having a better explanation of what those experiments and what those results mean. So people can better understand them. Any degree of uncertainty that can be open to different interpretation is immediately going to cause problems. So I think that science... scientists can actually have a better role in trying to explain what that information means. Not only in their papers, but also to the general public and to journalists, to make sure that the message is accurate, that what we're trying to say is, is this and not something else.

Simone Eizagirre 21:23

Yes, that's really, that's definitely really interesting. And I think that they're just thing but sometimes I feel like if you just take a moment to step back and think, Okay, what is it? What is this message? And, like, why is this message being spread to me is, is there someone -

Professor Stephen Baker 21:36

Yeah, and also, is it feasible, right? I mean, this this thing about, I mean, I don't- I don't even quite understand the whole 5G thing. I don't understand how, how a digital network can transmit a biological substance. I mean, I mean, there is got to be degree, some degree of feasibility about these things to which, to take a huge amount of common sense. I mean, you don't have to be a scientist to think that actually, you know, a some kind of transmitted signal can you know, can give you a viral infection? I mean, it doesn't make any sense. So there has to be some degree of plausibility. And for also, I think that that, again, one of the downsides of maybe modern life is that we're - we're very willing to absorb this information without making your own decision as well. I think we're, we're too busy trying to, you know, get all the information we can without really thinking about things and making our own decisions. So I guess, appealing to people to say, "Well, what do you think?" Just because, you know, is this believable or not? What's your opinion, just because someone else is saying it doesn't mean you necessarily have to agree with it.

Simone Eizagirre 22:37

And I guess, to kind of think about what's going to come next, what do you think are the main... because you were outlining the problem with like capacity, and also kind of not being able to have all these labs suddenly certified to make these diagnostic tests. But if mass testing is the way that we can kind of start to like de-escalate restrictions, then what do you think are the main barriers to that? How can we about solving them?

Professor Stephen Baker 23:01

While in the short term, I mean, there's been a lot of talk about ramping up testing. And I think that actually that, you know, ramping up testing is tough. And then who do you screen? When you screen them? I think that getting getting to grips with it now, hopefully, we are close to the peak in the UK. So everybody's talking about the curve- so hopefully we're at the peak of the curve or close to it. I think then identifying those cases, I think it will become key. As we move through, if we can get back to grips with it and get it under control, that we can start isolating people that are testing positive. So by screening more people as the disease goes down, what that allows us to do is is perhaps isolate those individuals more quickly. It will be a lower number of people that are testing positive as the disease decreases, but if we can get on top of those and identify them quickly, and get them isolated, then hopefully it will speed up the, the back end of the route, of reducing the number of cases we get, and get and get rid of it quicker. So that's going to be - that's going to be key.

Antibody tests are going to be key to get people back into work, to know who's been exposed. It's probably going to be important for international travel as well, probably. I can see it being feasible that we carry COVID immunity passports. So demonstrating that you have an antibody response, meaning that you're not going to be infected or you're not going to infect other people, is probably going to be important. And probably then longitudinal screening of people in vulnerable places as we try and get back people into work. I think that, I can see probably what will happen is that, depending on what you do and what your age group is, there will be a staggered introduction of normality again. And I think then screening those some of those key age groups in key working areas more regularly, self isolating those people when they are positive, will be really, really beneficial. But we have to detect them quickly and then get them to self isolate within to a specified period of time, because for every 24 hours you lose, there may be multiple more transmission events.

Ruby Coates 25:07

Yeah, yeah, absolutely. And obviously, we've already learned an awful amount about how to handle these situations, this situation already. It's horrible to even think about- but say, say an event like this happens again in the future. How do you think this, this pandemic could sort of prepare us for dealing with future pandemics, if they should ever arise?

Professor Stephen Baker 25:32

I mean, they [epidemics] arise systematically, don't they?

Ruby Coates 25:34

Yeah.

Professor Stephen Baker 25:35

I mean, I guess on the spacing of them would be the next thing. So yeah, how are we prepared? Um, well, I think there'll be, I think, in the kind of post-mortem of this event, when we kind of, you know, when the dust settles and we look back at what's happened. I think we'll, I think politically we'll look back at the negative parts and perhaps they will be focused on, but there are lots of positives about the way things have worked. I think, what will we learn? I think we'll learn a lot. Whether we can respond to those things, I don't know. I mean, we will be better prepared for knowing what to do when they come along. So we'll have better processes in hospital, there'll be probably more additional screening capacity set up earlier, we'll be probably more vigilant of watching what's going on with infections in other countries, to be aware that they could end up here. Without thinking, well, that's probably someone else's problem at the moment and probably don't need to think about it.

In hindsight - which is kind of, the greatest political tool - it would have been smarter to have things in place at the beginning of the year when there was cases ramping up in China, assuming that was going to happen. But that's a big undertaking. It's a big political effort. It's a big financial effort. And could we have done things a lot differently? I don't know. Getting people off the streets in the UK when they perceive the threat to be very small or non existent because it's not in the country, would be an enormous political headache. And it would be really, really, really impactful on society, of people not interacting one another, on the basis of no perceived risk. It was only really when the cases started to ramp up, that the government made the decision. And we could argue that it was too late or too early. But it would have been really difficult to impose those regulations. And until we knew what was really going on, and unfortunately, probably, it took a lot of cases and a lot of people to start dying for people to realise that this was serious, and they need to start doing what they were told. Without that, would that have happened? Probably not. So I think we have learned a lot and I think some some things will be changed, but I could see that actually, we would handle it better, but probably would follow pretty similar principles to what's happened this time.

Simone Eizagirre 27:41

Well, we don't take up any more of your precious time from doing the testing. Thank you so much for speaking just today.

Professor Stephen Baker 27:48

No problem - we've got some running now. Actually, we've got some coming off the machine so I've got to report those back.

Ruby Coates 27:53

Excellent. Well yeah, thank you so much for chatting to us! And thanks so much for [our listeners/readers!] for tuning in today, we really hope you enjoyed the podcast with Professor Steven Baker and learning a little bit more about COVID testing, as well as being able to be a bit more critical about the information that is sort of floating around. It'd be great if you could get in touch with us if you'd like to. We're on twitter @bluescipod. And you can also email us at radio(at)bluesci.co.uk.

*Ending music*