Thomas Jones: Hello, and welcome to the London Review of Books podcast. My name is Thomas Jones. It’s Monday, the seventh of April. At the weekend I spoke with Rupert Beale, a Clinician Scientist Group Leader at the Francis Crick Institute, and LRB contributor, who wrote about Covid-19 in the paper a month ago. We talked about testing for the virus, about the work he’s doing on that at the Crick, also about antibody testing, drug therapies and vaccines, but mostly about testing for the virus itself.
Hello Rupert, and thank you very much for joining us again. It's the afternoon of Saturday 4 April and just over three weeks since we last spoke, and a month since you wrote your piece in the LRB. Michael Gove has just given today's government briefing. So, some numbers then, first of all. They say that 183,190 people have been tested, 41,903 have tested positive. Just over 15,000 people have been admitted to hospital with Covid-19 symptoms, 708 is the most recent daily deaths total, the highest so far, and there've been 4,313 total deaths. And all those numbers are only going to rise. Do they give an accurate picture of the crisis?
Rupert Beale: They do. There is one set of numbers which, in a way, is the most heartening and it matches with what colleagues are telling me on the front line, which is that the number of admissions to hospital in London where of course, the epicentre of the pandemic in the UK is – the numbers of admissions are actually plateauing at the moment. So that suggests that the measures that were being put in place two weeks ago did have some effect. And the NHS frontline at the moment is not breached. The capacity for ventilation is there, there is, at the moment, enough spare capacity for ventilation, for the projected rise in cases that we're seeing. And I think if you're looking for positive news, in amongst some very grim statistics, then that, that is the positive news. That I don't think the NHS front line at the moment is in danger of breaking.
TJ: And is that true for the rest of the country? Because the number, the number of admissions has gone up significantly in Yorkshire and other places hasn’t it?
RB: It has, and I think that the relative delay in the spread of this from London to other parts of the country – well, it's not quite an accurate way of describing it, but the relative lag in terms of the number of cases coming through to hospitals in different parts of the country has allowed those hospitals more time to prepare. And I think that’s been crucial because, in the initial stages, people were very unclear about the best way of doing simple things, like segregating patients. People are very unclear about what a positive test result really meant versus a negative test result. And so we, you know, we saw cases where someone would be tested for the disease, tested for Covid-19, the test would be negative and they were immediately put then into a clean, so-called ‘clean’, area of the hospital. And in fact, we know now that especially depending on the kind of sample you take and the time course of that sort of sampling, that that you can have false negatives. And so those patients were then subsequently testing positive and hadn't been being looked after with the correct level of personal protective equipment by frontline NHS staff. So, I think that, having your sort of procedures in place and making sure that nothing happens which would be the detriment of your staff and patients, is something that we're beginning to get right now in the NHS.
TJ: And is that because there are fewer false negatives, that the tests have been changed? Or that people know that a negative there is the possibility of false negative, so you have to treat anyone with symptoms as potentially infectious?
RB: Absolutely. As this condition has become much more familiar to people, and people have realised that occasionally it presents in strange ways, for example, some patients even seem to present with abdominal pain, and they've come through, therefore, to surgical teams who would normally deal with that. But it's recognised that abdominal pain can be a symptom sometimes, not often, but sometimes of Covid-19. And so people have become very alert to this kind of possibility now. And of course, that knowledge has been pushed out straight away to hospitals where they're seeing fewer cases. So my expectation is that in those hospitals where they are at the moment seeing fewer cases, so for example, where I live in Cambridge there are many fewer cases than there are in London the procedures are in place there to make sure that these kinds of problems that you really don’t want to happen, don't happen. And I think that will be crucial in the response, the sort of frontline NHS response to the pandemic. I think the huge weakness at the moment, and my biggest worry actually, is that because we're not testing our frontline NHS staff, we don't know how many of them are infected and we don't know if they're potentially transmitting this virus to colleagues and patients. That's my personal biggest worry at the moment. Really, we should be testing more or less the entire frontline workforce at regular intervals if they're likely to be exposed to the virus. At the moment, there's nothing like the capacity to do that within the system.
TJ: So what needs to be done to create that capacity?
RB: Well, this is a huge challenge right now, and this is something that, I'm now very directly involved with – something I did not anticipate, you know, three weeks ago. So there was a certain amount of testing capability that could just simply be run a little bit faster, a little bit more of it, in the public health laboratories around the country, and the NHS laboratories that Public Health England rolled out the testing capability to. The difficulty comes that of course we're in a situation where literally every country in the world wants to do as many tests as possible and therefore they all want the same reagents, they want the same chemicals, to perform these tests. And most of the tests that we do in the UK, in fact the great majority of them, are based on commercial platforms, which under normal circumstances is fine. Your reagents are all made up in a factory in Germany or wherever it is, and then they ship them over to you and then you get them as, more or less, solution A, solution B, solution C, and you do A, B, and C, and you get a great result. And, of course, they're all compatible within their own systems. The difficulty, of course, is that people had not anticipated that there would be this enormous global demand for all of these all at the same time, and so the initial ambition by the government, which was stated, they wanted eventually to run 250,000 tests a day, and they were going to do that in large, centralised testing centres. For example, in Milton Keynes, you know, they impounded, as it were, they took, for the time being, platforms to do this from research institutes and so on. But I think because of the lack, globally, of these proprietary reagents and the inability of these companies to produce not just tenfold more, but a thousand or more, more than that fold, more than they're used to. That's meant that the testing capability hasn't got up to where it really needs to be. So then you have to think around the problem. What we decided to do in the Crick, because we're doing testing now in partnership with our local NHS trusts, is to try and base our testing on the most, as it were, generic chemistry possible. So that we really didn't have to rely on external suppliers of reagents that only they in principle can produce. Now, most of these reagents and chemicals are pretty simple to make. So you know, simple stuff if you've got the right chemicals. So I found myself over the past at a couple of weeks being part of this effort in the Crick, and one of my jobs is to work out the best way of inactivating the virus and also preserving the genome of the virus, the RNA bit of the genome that you need to, to run the test. And of course, I've run a lot of PCR reactions, these kinds of tests in the past at very small scales. How do you scale this up massively? Well, you need advice from people who do this professionally and who've got the expertise to tell you what the best sort of way of doing it might be. And actually we've got some fantastic advice from Public Health Wales who were really helpful about a good way of inactivating the virus that will be safe. Because of course, the absolute last thing you want to do is infect anyone who's carrying out these tests – that would be a disaster. And then of course we went to observe our local NHS testing labs and they are getting the samples in multiple different formats. So then the next challenge is to make sure that no matter what format you get swab in, because people are running out of swabs, they're running out of proprietary swabs, they're making their own swabs. I mean, the swabs are basically a glorified cotton wool bud. But some of them need to be in special viral transport media and others can be dry and so on. So, again, great advice from Public Health Wales about a process that you could essentially put all of these different swab formats into one inactivation set of chemicals. So we made that up and basically it started to work first time, which was fantastic. And then there's been huge effort from a whole bunch of people who do things like programme robots, who run the sequencing facility in our institute. They've repurposed their robots for this. We've sorted out lots of barcoding issues. We track patient samples and the IT people helped a lot with this. And then we have a high throughput screening facility, which usually is looking for, for example, new chemical inhibitors of a pathway for scientific research, and they basically repurposed what they're doing to look at the constitutive PCRs. And we did this all in partnership with our local, UCLH testing laboratories and the virologists there. So there's been an enormous effort, with a huge number of people, and it looks to be working pretty well. So at least for small numbers of samples, we can certainly do this. We ourselves are now trying to ramp this up. It's a cliche to talk about ramping things up, but I apologise that I'm going to say ramping up at all times.
TJ: It’s no longer a cliche, it’s just the word.
RB: It's just what people say. So we know we can do this at small scale. Our big challenge is, can we do this at a large scale? And can we do this ultra reliably and can we do this for the next, you know, three, four months.
TJ: And presumably, if you could do this, and the whole point of this is to do it as generically as possible, if you're able to do it at the Crick then other labs will be able to do it as well.
RB: So that's the idea and we're going to share all our operating procedures and everything like that with anybody that wants them, and each institute that's doing this will have to work out the best way of doing this for itself. But the key for us was working very closely with local NHS laboratories to make sure that we were giving comparable results to them, that we weren't having false positives and false negatives, because I mean, you get false negatives principally because of a sampling error. The swab doesn't go far enough or something like that, but we of course also need to make sure we don't have an additional set of false negatives or false positives introduced by, as it were, the molecular biology. And I think we can be pretty confident the molecular biology is working very, very well. And so then the next challenge that we're going to start working on is whether or not we can improve sample collection. And we've got ideas about that as well. And hopefully we'll be able to, again, work with NHS trusts locally to implement better sample collection and so on. So we're basically going to do whatever we can do to make sure that we're delivering the tests as accurately as possible. And then the other crucial thing is speed. So if you're doing a test in Taunton and you have to send it to Milton Keynes for testing, that's obviously an intrinsic weakness in the process. So I think the government's new strategy for testing, which seems to be much more plausible and I really hope we can manage to help deliver this, is to, so as it were, distribute the testing capability around more centres, so these can be done more locally and not to have a sort of monopoly-type system where you're only using this kind of chemical, only using that kind of chemical. Because what happens if you run out of that chemical? Well, now you're in big, big trouble. And that could take out, you know, 50 or, in principle, 100% of your testing capability, if something went badly wrong, But if everything's, as it were, distributed, then, okay, maybe our institute's messed up and we can't do any tests for a couple of days, but at least the one 50 miles away can.
TJ: So testing is really the only – mass testing is the only solution to that.
RB: Well, it's not the only solution. I mean, the other things you can do, you can have very careful barrier nursing techniques. That of course, relies on having large amounts of personal protective equipment, PPE. Of course there's also problems in the supply chain there. So I think it's a question of both/and, not either/or. A belt and braces type approach to patient safety and staff safety.
TJ: And do you, do you have enough PPE?
RB: Well, we need almost no PPE, because the process we have designed is unbelievably safe. And again, this is from Public Health Wales. So what we do is we do all of our own activation in the category 3 labs. So that's one step away from category 4, which is ebola and stuff like this. We do all of that in category 3 labs. So what we need is, so there's an air flow here, so you don't need to wear a mask. airflow here, which is, you know, shutting it all out. You're wearing gloves, you're wearing a standard laboratory gown, and then you wear a sort of sleeve that goes over from the glove to here to make sure nothing gets onto you. But a droplet will be absorbed quite well by a lab coat and it inactivates the virus more or less straight away by dehydrating it. We're getting most of our samples with dry swabs rather than wet swabs. The dry swabs also more or less kills the virus already. So then we've got a dry swab, we stick it straight into this five molar guanidinium solution with soap, virus is dead. Out goes the swab into a waste bucket, which is full of lethal bleach type stuff. Screw the top on. Turn around and around, wipe it around the outside, hand it to your mate, they wipe it around the outside, and then it gets worked around the outside again, further down the line. So you know it's dead inside and you know it’s dead outside. So the minute it comes out of category 3 it can be handled at category 1. So all that you need to do is use a white glove.
TJ: And also as they were able to do in South Korea, that as well as the testing, you then have to do contact tracing and isolating. And it's what you do with the test results, isn't it?
RB: Absolutely. So Steve Powis in this interview said he doesn't like the term ‘exit strategy’, and actually I do see where he's coming from on that. And I was about to say this is going to be an important part of the exit strategy, but I, I liked the way he wanted us to rephrase that and I think it will become a really important part of managing this disease and what you might call a sustainable way or a way that isn't going to completely collapse either the economy or the NHS. Because you can't maintain lockdown measures indefinitely. Everyone knows and accepts this. So it's a question of how you most precisely relax those lockdown measures. And of course, if you've got really good information about who's infected and what the symptoms are and its duration in your particular population, and what measures have worked where and what kinds of social distancing turned out to be really important in this setting versus that setting, if you've got that data, then you can do that in a kind of more rational way, a way which you're less likely to spread the disease and more likely to be able to improve the economy. And, of course, the contact tracing can be done in principle, certainly, by mobile phone technology.
TJ: There are privacy considerations.
RB: Well, there are privacy considerations, but on the other hand, there's also a massive public health consideration. And one has to set this aside, not fully, but to some extent. So the people who are working on this, I think, are very credible and serious people who've taken the privacy issue very seriously. Because. The risk issue to me is – of course, I see it from the point of view of a doctor – the risk is that if you don't put in place robust privacy then you will lessen the uptake of whichever mobile phone app tracing you eventually go for. If people can be confident that their data is going to be stored securely and isn't going to be shared with people other than other than for public health measures, then I think people can have confidence that essentially it’s no different to giving your name and address and many other personal details to your doctor, which of course people are happy to do. I'm of course not working on this myself, but I know some of the people who are, and I'm sure this is very high up in their considerations.
TJ: And in terms of other things that can help with the, not the exit strategy, but with allowing life to continue. In the face of Covid-19 there's quite a lot of talk about developing antibody tests as well, to see who has had it and may have some immunity to it. Where are things on that?
RB: So it's one of the most curious things about the entire pandemic from start to where we are now, and possibly until finish, is that people are not paying enough attention to the way in which people are acting. By which I mean governments. If it had been tremendously easy to develop a mass-produced antibody test, that would already have been done and it would already be being used in China and South Korea, for certain. So I think we can be pretty clear that it's not easy to develop an antibody test that will be easily deliverable in a very high throughput. way, in a short period of time. What there certainly is, is the ability to look for immunity. I say immunity – to look for antibodies, which have been raised against SARS-2, in a small throughput format in decent laboratories. And so, again, the government's strategy on this strikes me as rational in that they are testing a number of commercially produced, point-of-care antibody tests and benchmarking them against carefully implemented laboratory standard serology tests being done at Porton Down by Public Health England. The big issue that may well be arising, and I suspect is the reason why none of these tests have yet proven to be effective, is that there will be a degree of cross-reactivity with some of the SARS-2 proteins with what we call seasonal coronaviruses. In other words, the viruses that cause essentially common cold-like symptoms that everyone will have had once or twice or perhaps more often in their lifetime and to which they will almost certainly have raised some antibodies. And the problem is if everybody has antibodies to these seasonal coronaviruses and only a small proportion of people have antibodies to SARS-2, then even if you have a 1% cross-reactivity, you'll be reassuring falsely a very large number of people that they're immune when they're not. It will become very important at some point to know who's been infected. And of course, it would have been very nice if we'd had that information already by having a mass programme of testing, the PCR-based test that detects the presence of the virus now. Like I was saying, the difficulty is not in constructing a test that works, the difficulty is in constructing a test that works and can be made available on a very, very large scale.
TJ: But for doctors, for example, if you could have a test to allow doctors to go back to work, to frontline NHS staff being able to return to work safely.
RB: Yes, so you could imagine a useful setting for the various labour-intensive, small scale laboratory testing. It would be nice, for example, if you knew, you know, which of your A&E and intensive care staff, for example, were likely to be immune, that would be helpful information. I suspect we will have a mass market point of care test that does work in the future. My guess is that this will be as a result of people looking at multiple different SARS-2/coronavirus proteins and only giving you, as it were, the thumbs-up, the all clear, in terms of immunity, if you've raised antibodies to all of these different proteins and not just one where you might be unlucky and have a cross-reactive antibody test with a different virus I suspect we will get there. My guess is that all of the early models will fail, but I could be wrong, the NHS is going to test them. But I would be surprised if we have tremendously useful information at a population level n the next few weeks. I think it'll be more likely months, but who knows, I could be wrong.
TJ: And the vaccine will take even longer.
RB: A vaccine for certain will take even longer. My naive prediction is that this will be one of the fastest developed vaccines ever in the world when it does come through, because it may be difficult to develop a vaccine because of the biology of the virus, but, on the other hand, it won't be for lack of people trying, and this is one of the very, very few situations where people will be keen to go more or less straight from small scale animal trials to human trials.
TJ: And there've been news reports that some have already started, they’re already starting.
RB: I believe that's the case, yes. The huge worry, the, as it were, worst-case scenario, and I don't want to alarm people too much, because I think this is relatively unlikely. The worst thing that could happen is you develop a vaccine that unfortunately makes the virus slightly worse. That, in principle, could happen if you're tremendously unlucky, or if you’ve made an error, a bad error in the design of the vaccine.
TJ: And that’s a reason to be careful in vaccine development.
RB: It’s a reason to be very careful in vaccine development. It has happened in the past for other viruses, and this is, of course, is why you have to test the vaccines carefully before you can recommend them. So, impossible to predict exactly when a vaccine will become available in a, on a very large scale. Most people would think it would be a year or more. There is a chance if we're very lucky that we'll have something which is useful before then.
TJ: And there's also the question, the other drug angle, as it were, is in terms of the therapies to relieve symptoms.
RB: Yes, there are a number of things being tried at the moment. Honestly, I don't hold out a huge amount of hope for most of them. I mean, the one that everyone's been talking about is hydroxychloroquine. Which, of course was promulgated by what I think most people would regard as an extremely poorly conducted study in France and then subsequently by Donald Trump. The evidence so far is not in favour of that. There are professionally designed, much better trials ongoing, including in the UK, that will look at that as a potential strategy.
TJ: But it was developed as a malaria treatment.
RB: Yes, it was developed as a malaria treatment and we use it in the laboratory all the time for all sorts of things. It has very interesting properties in terms of how it alters cell biology and it ,more or less, always blocks viruses that enter cells in a way that depends on acid, because essentially it's neutralising acid inside the cells, and then if the virus can't get in because there's no acid, it can't get in, so you can inhibit replication of the virus. Now, whereas it works for just about every virus in a test tube, so far, it works for zero viruses that we've ever tested in humans. So it wouldn't be my, as it were, first sport of call if you're looking for a hopeful antiviral treatment. We could be lucky, maybe it does have an effect on this virus. If it does, fantastic. And it'd be important information to collect. It's not a particularly toxic drug unless you use it in very high concentrations, although it does have potential side effects that people need to be aware of. So I wouldn't regard it as a most favoured hope.
TJ: From what you've been seeing so far in terms of testing for the virus, testing for possible immunity to the virus, developing therapies, developing vaccines, scientifically, most promising of all of those by some distances, testing for the presence of the virus and then acting on that.
RB: Well, it's the most promising because it's the most proven and it's extremely reliable. At least the molecular biology of it is extremely reliable. It's not to say you can't run into problems. And it's been part of the, so far, very successful South Korean strategy, and in South Korea, they're reliably having roughly a hundred new cases detected a day. And they can be pretty clear it is about a hundred new cases because they're testing so much.
TJ: Why do they have the testing capacity, which most other countries don't have?
RB: Because they thought about it in advance. It's as simple as that, in a way. They had a plan in place already because they had experience of SARS and MERS, which are related viruses – SARS the first of these to be discovered was particularly devastating within hospitals. A very high mortality rate, but fortunately for everybody, it wasn't particularly transmissible. What we've got with SARS-2, is a virus which has a much lower mortality rate than SARS-1 but it's much more transmissible. And that turns out to be much more difficult to deal with. But the Koreans had a very good plan in place to deal with this, so when they did have their outbreak, which was centred on a large ’super spreading event’, as they say, they put in place a very rapid contact and trace programme. They had developed and validated their qPCR systems. And there was just a lot of hard work and dedication by all the laboratory scientists and staff there.
TJ: And so in a sense what other countries are doing now is catching up as quickly as possible with South Korea.
RB: That’s right, it's the old cliche, the old adage, if you fail to prepare, you prepare to fail, and I'm afraid to say that's the position that a lot of Western democracies have found themselves in. I look back on the article I wrote on 6 March when I suggested that most Western democracies would follow the Korean model. I wish that had been the case. I mean, it's clear that many of them didn't or didn't even try until several weeks later when it became obvious that this was the only – or almost whatever your strategy is, really large scale, rapid and efficient testing was going to have to be part of it. And it's not just in the United Kingdom, but many other parts of the Western world that these preparations simply were not made in an adequate way. But I suppose, in a way, that's irrelevant, we are where we are and we just have to soldier on as best we can. It certainly gives a certain amount of hope that the sort of model that's in South Korea could be to a large extent replicated in many Western democracies. If we can get on top of the first wave of the epidemic and if we managed to implement a carefully thought-through testing and tracing and strategy the strategy advocated by Professor Neil Ferguson, on the Today Programme this morning. And I'm very glad that his voice carries a certain amount of weight within government thinking on this topic. Other strategies are available, but I'll recommend Professor Ferguson.
TJ: And on that recommendation, Rupert, thank you very much. imagine that we may well be speaking to you again in a few weeks from now, with luck with – well, not with luck, with the immense amount of hard work everyone's putting in, with better news. That's great. Thank you very much.
RB: Nice to talk to you.
TJ: The new issue of the LRB will be out shortly, on our website and other digital channels on Wednesday, and reaching subscribers as soon after that as delivery services allow. A couple of pieces from it are already online: Lana Spawls on how to set up an ICU, and James Butler on the government’s response to Covid-19. Other pieces in the issue include Adam Tooze on the consequences of the pandemic for the world economy, and Wang Xiuying’s latest report from China. It isn’t all coronavirus: there’s also Joanna Biggs on Simone de Beauvoir, and Jeremy Harding on Extinction Rebellion.
