Covid Science: Test, Track, Trace

We're unpicking the science of covid testing, monitoring and tracing this week.....
07 July 2020
Presented by Katie Haylor, Chris Smith
Production by Katie Haylor.

TEST-TUBE-COVID

Covid-19 sample test

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This week, testing, tracing and monitoring. How does a covid test actually work? Do antibodies to covid mean immunity? And the tech to monitor covid symptoms from home. Plus in the news, as lockdowns go local: how are they doing it Down Under? Why planting trees to capture carbon might not necessarily be the best move, and the sparrows changing their tunes!

In this episode

A map of the world showing hotspots of an infection.

Leicester and Melbourne - lockdown again
Freya Jephcott, University of Cambridge; Philip Russo, Monash University

The city of Leicester has been making the headlines this week. Unlike the rest of the UK that celebrated Super Saturday as the lockdown eased, there was no grand re-opening for their pubs; schools have been restricted to children of essential workers again, and non-essential shops have had to pull down their shutters, because, owing to a surge in coronavirus cases, the lockdown has been extended there. Nobody seems to be able to put their finger on precisely why Leicester has come top of the league for coronavirus cases this last month. The Department for Health and Social care said there were “multiple” factors causing the spike and that there were no quote: "care homes, hospital settings, or industrial processes”  that would immediately explain the apparent rise in new diagnoses. But scientists say infections may reflect social inequalities: in places where there are more white collar jobs, employees can work from home and isolate from others. In more deprived areas, on the other hand, people are more likely to have to go to work and use public transport, raising their risk of becoming infected. Cambridge University’s Freya Jephcott studies disease outbreaks, so what does she make of the “longer lockdown” approach to controlling the outbreak in Leicester? Freya spoke to Chris Smith...

Freya - I think in general terms, we're already sort of on the right track. It's really about empowering local health authorities now - when we do see increased transmission in specific areas - to act in a way that they know is locally appropriate and also locally effective to contain it. Because the way outbreaks spread is obviously determined a lot by the population it's spreading in, the sort of density of the housing arrangement, the kind of industries they rely on for the economy there.

Chris - Do we actually know what is the right way forward though? In terms of when you have these sorts of combinations of factors, what the right thing to do is? Or is it going to be a learning exercise and different cities with different formats, different population groups are going to have to learn the hard way and then they'll know for next time?

Freya - Absolutely. Especially with such an unfamiliar and new virus, there is going to be a lot of trial and error, a lot of trying to learn from each other and also trying to look locally to see what's going to help. There is not going to be a one size fits all. And I think the fact that nothing is certain should be a bit reassuring in that there is discussion and research, and that's really what's required at present.

Chris - Given it is summer, and we know that viruses spread much less well in summertime when more people are out and about. We're also in the immediate aftermath of a lockdown when arguably the amount of virus circulating should be extremely low. Is it not rather worrying that we've got Leicester happening right now?

Freya - It's obviously concerning. I'm not sure whether we should see it as entirely surprising. There are a few features of a city like Leicester that would leave it a little more susceptible to ongoing transmission. What encourages me is that it was detected and that there is this discussion now of maybe some kind of local interventions that could come into control. There is something to be said for the fact that it is summer and there does seem to be less transmission that occurs when you're in open spaces. So maybe there is some kind of happier middle ground of opening up that is possible with something that sort of leverages the fact that we can be outside right now and not be rained on or chilly.

Chris - We've now got plans being laid for opening up the hospitality industry more, opening up air bridges to other European countries. What are your feelings on the direction of travel? Is it too much too soon, or do you think this is about right?

Freya - I think it's important in answering this question that I make it clear that my background is very much coming from the epidemiology anthropology side. I'm not an economist, I'm not a public policymaker as a rule, but from my perspective, it is worrying. I'm sure that there are ways that we can support hospitality industries to open up in a way that sort of mitigates the risk. And so I'm hopeful there. But the issues around international spread do concern me, not just the idea of importing cases into Britain if we get transmission even lower, which could trigger new ongoing transmission, but also the fact that we might be exporting cases to vulnerable places. We've not only got to think about risks to our country, but the role we play in sort of proliferating this outbreak globally too.

 

And speaking of the international situation, in Melbourne, Australia’s second biggest city, in the state of Victoria, the government there have imposed what appears to be a much tougher local lockdown than the one in Leicester. The finger in Melbourne is being pointed at security guards who’ve been blamed for a spike in cases by allegedly catching coronavirus through having sex with international travellers quarantined in a 5 star hotel in the city. Monash University’s Philip Russo spoke to Chris Smith...

Philip - The past 10, 11 days, we've had an increase of daily new cases of covid infection. The evidence has shown us that they're confined to a certain few suburbs in Melbourne. Some genomic testing has demonstrated that most likely they are due to a breakdown in infection prevention in the quarantine hotels that we put returning international travelers in.

Chris - What do you mean by that? There are people who were admitted to those venues and they've unfortunately spread it beyond them?

Philip - Returning international travelers are quarantined here for two weeks on arrival. And they've been put up in hotels, staffed by security guards who have been employed to ensure the travelers remain inside the hotel. But it appears as though the security staff haven't been following the infection control guidelines. The security guards have become infected and then subsequently taken it back to their areas of residence and into the community.

Chris - How many cases has Melbourne got now and over what sort of timeline?

Philip - About two weeks ago, we were having zero cases on a daily basis. And at the moment we're having in excess of around about 60 to 70 new cases per day. Which possibly doesn't sound like a lot. But then compared to the other states in Australia who are having zero to one or two cases on a daily basis for a number of weeks now, it certainly stands out.

Chris - What has been the reaction of the government to this?

Philip - The Victorian government has been very proactive in responding to this. And as of midnight tonight, Melbourne time, there are 10 suburbs around Melbourne who are going back to stage three restrictions. People in those 10 suburbs will only be allowed out of their houses for four reasons - essential shopping for food and supplies, caregiving, to exercise and to study or work if they can't do that from home.

Chris - And how long is this going to go on for?

Philip - So at this stage, um, the government is saying that this is going to continue on until at least the 29th of July, so about four weeks. But it's possible that if we continue to get an increase in new cases, that time frame may be extended. We are doing extensive testing in those suburbs, but also we have free testing across Melbourne. The likelihood is if we start to see cases outside of those areas, then the number of suburbs that go into that stage three restrictions might actually be extended.

Chris - It's a stark reminder isn't it? Because Australia has had a very good track record of dealing with Covid. The testing was very fast off the board, done at enormous scale, it's an outlier in that respect. And it just serves as a reminder that no one is above Covid.

Philip - And that's the message we're trying to get to the community here. On an international scale, we've done reasonably well, but the message we're trying to get across is that it's not over, this is a marathon. It's not a sprint. We're somewhere in the marathon. We actually don't know where we are. We might not even be halfway at this stage. And so what we're doing now, it's more than likely that we'll continue to see these clusters, these little outbreaks here and there, possibly up for the next 12 to 18 months. We're confident though that the amount of testing that we're doing and our public health response should be able to limit the spread of infection to a large degree.

photograph of a forest

10:05 - Tree plantations and carbon capture

Tree plantations aren't necessarily good for the environment...

Tree plantations and carbon capture
Robert Heilmayr, Bren School of Environmental Science and Management

Over the past decade, planting trees has become an option, backed by governments, to capture carbon dioxide in the fight against climate change. But a new study shows that this can leave the planet worse off than it was before. Researchers have analysed the effects of a long-running campaign in Chile to subsidise tree planting. And as Phil Sansom heard from Robert Heilmayr, the resulting ‘plantations’ weren’t good news...

Robert - In many cases, those new plantations were encroaching upon native forests and shrublands. And so that conversion of native forest to plantations really led to a reduction in biodiversity across the landscape and an undermining of the carbon benefits that we would hope we would get.

Phil - Really? So in this case, planting trees ended up bad for the environment.

Robert - Yeah. What it ended up highlighting is that it really depends how you go about planting those trees, right? If you're replacing some of the existing standing forest that's been growing for centuries and replacing them with kind of young plantation forest that you plan to clear within 20 years, obviously you're not going to get as much carbon in that above ground biomass that you would, if you just left those forests standing.

Phil - Can you explain that? I'm not quite sure I understand the whole biomass concept.

Robert - Yeah. So, you know, all vegetation is made out of carbon. And so as plants go through photosynthesis, they're storing carbon in their structure. One of the ways that people think a potential contribution to addressing climate change would be to increase the amount of vegetation out there. We're kind of increasing the storage of carbon.

Phil - Basically more tree, more tree material, equals good.

Robert - Yes. That's usually the case. Yeah. And so what ends up happening with this kind of plantation setting is that you have less tree material, less plant in a forest than you would within kind of a natural dense native forest.

Phil - That's kind of perverse though. Why were people chopping down beautiful old forest just to plant a new single type of tree?

Robert - I mean, the initial intent of the policy was largely to build kind of a domestic timber sector. This was implemented under the Pinochet regime in the 1970s. And they were really looking for ways to kind of drive economic growth. But at the same time there were environmental concerns in this kind of central and Southern parts of Chile. There were large areas that had been degraded through, um, really aggressive agricultural practices. And so the government felt that if they encouraged people to reforest those landscapes, they would reduce the rates of erosion and help kind of reclaim some of these lands that were really marginal and not being put to use. The problem with it was that it, although they initially had a policy in place that said, "you can't convert native forest to plantations and get the subsidy", they were really poorly enforced. And so you had a lot of cases where you were actually getting the kind of conversion of a native forest to agriculture for a year, maybe a pasture, and then people would apply for these subsidies and convert it to plantation forest.

Phil - And then if the point was for timber, were people just getting paid to plant trees and then chop them down again?

Robert - Exactly. So they do provide some soil erosion protection. They do provide some carbon benefits, but the main goal of those plantations is really as a feedstock for large pulp mills and timber mills that exist in Chile.

Phil - Can you then compare this to any of the big tree planting campaigns that are going on today?

Robert - We don't necessarily think that planting trees is a bad idea. It can be, and I think it will be an important part of the solution to climate change. However, our study really cautions that you want to design the policies in a way that doesn't lose a native forest at the same time. We want to be reforesting landscapes with kind of the native species, not an unending kind of row by row monoculture of one species of trees.

Phil - It reminds me a little bit of the whole biofuels thing, where people thought "here's an environmentally friendly fuel. It just grows out of the ground", but in reality, it takes precious land to grow that biofuel. And then you're just burning it anyway.

Robert - Yeah. I think that's true. And even, you know, in the timber sector, a growing trend right now is to use wood pellets for home heating. And I think that's especially common in Europe. And what you're finding is that in some cases, those wood pellets are associated with clearing of natural forests at a pretty large scale. I think policy makers today are making some of the same mistakes that we saw happen 40 years ago. When you look at the commitments that people are making in things like the Bonn Challenge, which is one of these kind of global reforestation campaigns, almost half, I think, of the commitments under that are to replant with plantations.

 

DNA and molecules

16:19 - Uncovering immunodeficiency genetics

What can reading genetic codes reveal about inherited immune diseases?

Uncovering immunodeficiency genetics
Ken Smith, Cambridge University

How the immune system works, and the role of our genetic makeup in causing a range of inherited immune diseases including autoimmune conditions, allergy and increased cancer risks, have been revealed by a landmark study from researchers at Cambridge University. The team have read the complete genetic codes of over 1000 patients with these sorts of disorders to link the genes they carry with the diseases they develop. Chris Smith spoke to Ken Smith from the Cambridge Institute of Therapeutic Immunology & Infectious Disease...

Ken - We did this by studying a group of patients with defective immune systems, with conditions called primary immune deficiency. And these patients are susceptible to infections, often very severe infections: about a third develop inflammatory diseases, and about 10%, various sorts of cancer. And this is caused by genetic problems, but in the vast majority of patients with these conditions, the genetic cause is not found. So what we did was to recruit a very large number of these patients from over 27 centres across the UK; we ended up with more than a thousand patients, which is more than a third of patients with this condition in the country. And we sequenced their entire genome rather than the usual approach, which is to sequence just a small proportion of it. By doing that we could then discover new genetic causes.

Chris - I get that you got these patients, you know they have a condition that unites them, and that you read the DNA end to end. But if you read a book from end to end, you wouldn't necessarily know which chapters were the ones playing the role in the story that you're referring to. So how did you link the diseases these people had with what the genetic code was saying?

Ken - What we did was to look for mutations or variants that were present in patients with the disease, but were not present in a large number of healthy people. If a few of these very rare mutations were found in a gene in patients with immune deficiency and were not found in the normal population, that made us very suspicious that that gene was involved in causing immune dysfunction. What we then had to do was go to the laboratory to prove the association of that gene with immunodeficiency. What that did in this study was to allow us to find more than five new genetic causes of immune dysfunction, with many more, I think, still to come from the study.

Chris - Why was this missed before? It's pretty straightforward what you've done, in the sense of reading people's genomes. Why had no one thought to do it the way you did it?

Ken - I think they probably thought to do it, but it's only become affordable recently. Until recently it was impossible to sequence whole genomes at scale, as we've done. But through the national BioResource rare diseases programme, it's become possible to afford to sequence patients. The second thing is the statistical approaches, headed by Ernest Turro and others, that have allowed us to analyse such large numbers of genomes. So it's a technical advance rather than a philosophical one.

Chris - Obviously it's very useful for patients who have one of these conditions, because it means you can give them almost a more precise diagnosis. But is it true that when nature makes a mistake in this way, sometimes some of her other inner workings are revealed? That's kind of the old saying, isn't it. Have you learned more about how the immune system works in a healthy person by studying a less healthy person?

Ken - We have. We've found a number of genetic pathways involved in causing these problems with the immune system, that we have evidence are involved in much more common diseases as well. And by finding that information out, we can study more about the immune system in general. What we've also done for the patients who get the diagnosis is put them in a position to plan their lives better; understand the implications of their disease for their families, which is often not known until they have a genetic diagnosis; and in many cases, to allow specific treatments for the disease that wouldn't have been possible without a diagnosis.

 

picture of a white-throated sparrow

Canadian sparrows have changed their tune
Ken Otter, University of Northern British Columbia

Researchers in Canada have found that there’s a new hit song sweeping the country - at least among the nation’s white-throated sparrows. When biology professor Ken - another Ken - Otter moved to British Columbia in Western Canada he was surprised to discover that these small and noisy birds were singing a very different tune to their East coast colleagues. And as the years went by, recordings sent in from citizen scientists all over Canada showed that this west coast new song had gone viral! Eva Higginbotham spoke to Ken to find out more...

Ken - What it is is at the beginning of the song, the males have an introduction that has three whistled notes; very clean, pure-sounding notes. And it's supposed to... it's very patriotic in Canada, at least the description of it is that they're supposed to be singing, "my oh my, sweet Canada, Canada, Canada, Canada". And so that ending phrase is a repeat of three repeating notes with a little gap in between them. So it's "da-da-da, da-da-da, da-da-da," like that. And the males will sing that a variable number of times. That's the classic triplet ending song.

Eva - And you've actually sent me some recordings of that. So let's have a listen and hear what that sounds like, the triplet.

[BIRDSONG]

Eva - Okay. So I can hear the Canada, Canada, Canada. That's the classic - what's the new one?

Ken - That's the classic. The one that we found: instead of singing three notes, they sing two notes; it's kind of a long note-short note, long note-short note, with not much of a space in between it. And then they ended on a long note. So it kind of goes, "can-a can-a can-a can-a Canada," like that. So it's like they're stuttering the whole way through it.

Eva - Okay, cool. Let's give that one a listen too.

[BIRDSONG]

Eva - Uhuh, okay. So the song seems to have originated in the west of Canada and now is traveling east?

Ken - It was still the common song type in the east, across the eastern range of the birds, was the triplet ending songs in the early 2000s. And between 2000 and 2019, the doublet ending song spread across Canada and took over; it completely replaced the triplet ending song. So it's travelling across the country at quite a rapid pace and it's completely replacing the triplet song wherever it's taken a foothold. What was happening is our birds, in British Columbia, were overwintering with birds that were singing a totally different song type. And we started to look to see whether there was a possibility that the birds were singing on these wintering grounds and potentially serving as tutors for juvenile birds that bred and other populations. And that could explain how the song actually spreads from one population to another.

Eva - And so this was essentially a mixing of birds from the west of Canada with the east of Canada. They all head down and mix up and overwinter together.

Ken - That's basically what we found, that the birds do sing on their wintering ground, and we started to see this western dialect popping up in the eastern wintering grounds. But what's strange about this is that we're having situations where males are coming in and they're singing this new song type, the doublet ending song, and instead of converging on the common song type in a particular area, these few males that are settling suddenly become the template, and other males start adopting that song and it starts to spread in the population. And so the new song type starts to take over. It would be kind of like an Australian person coming to Cambridge and everybody suddenly adopting an Australian accent, and everybody starting to sound like Australians in Cambridge. And that's essentially what we're seeing here.

Eva - So what is special about the doublet sound that has made it take off so well?

Ken - I don't know specifically what it is about the doublet. It may just be that it's slightly different. And there are certain templates inside the bird's head that when they actually hit on that new song, it's acceptable, but it's novel. And that's what we think might be driving this: that they're picking it up just because it sounds slightly atypical, but it's still within the acceptable limits of what the birds recognise as an acceptable song. And so occasionally these things might pop up, and then if they're broadly adopted, then it just sweeps through the population quickly.

Eva - So it's sort of the cool new tune, which is not so far out that the birds will be put off by it, but it's different enough to sound cool and interesting.

Ken - Exactly. And so that's what we think might be happening. Because there doesn't seem to be a big disadvantage to sing one of these new dialects if you're trying to establish yourself as a territorial male. So we think what might be happening is that the females might actually like these slightly atypical songs, and that could be driving males to adopt them. But that's something that we still have to test.

a picture of a medical swab

29:06 - How do swab tests work?

How do the "do I have Covid now?" tests actually work?

How do swab tests work?
Ravi Gupta, Cambridge University

As of early morning 2nd July, nearly 8 million tests have been processed in the UK. The vast majority of those were molecular tests, so-called swab tests, which can reveal if you’re currently infected with coronavirus. A swab is taken from the nose or throat, and the test looks for specific genetic material that indicates the virus is there. Ravi Gupta is a physician at Cambridge University and he’s been working on speeding up tests like this. He spoke to Katie Haylor about how they work...

Ravi - It's based around trying to pick up or detect small amounts of the genetic material of the virus, which of course is present during an infection. The method relies really on making large numbers of copies of what's already there because of course what's already there can be very small and we need to make the signal very large in order to detect it. And so that's called nucleic acid amplification, and that's exactly how most tests are developed and function. So these can be fairly complex or they can be more simple. And we've been working on a simplified version that instead of taking three to five hours to run, we'll be able to give your results in about 75 minutes. This particular platform is called Samba two. The reason it's very successful in terms of the technology and how quickly we've been able to implement it is because this is a machine that was really developed for monitoring HIV in Africa, and to give a robust, quick result in a very sort of sturdy platform. And it's been tested and tried over many, many years. And so what the inventors did is to adapt it for SARS coronavirus two, which is the virus that causes COVID-19. And so the new chemistry was developed very rapidly and we had the opportunity to test it at Addenbrooke's hospital in around 200 patients in a trial that showed that the test was equally as good as the existing test in the lab.

Katie - And what is this new chemistry that enables it to be so much faster?

Ravi - So the new chemistry is based around the fact that traditionally we use something called polymerase chain reaction, and that basically needs temperatures to go up and down in a very precise way. And that takes time and we have these things called cycles involved. And the new chemistry really does something somewhat similar except performs things at the same temperature. And it's what we call isothermal. And that makes it much quicker and simpler to run.

Katie - How good are these tests? How worried do we need to be about false results, false negatives, false positives, stuff like that?

Ravi - In the trial that we ran, where we put the Samba Two rapid test against the hospital laboratory test developed by Public Health England, our test was 98 to 99% sensitive. In other words, picked up 99 out of every 100 positive tests using the standard laboratory assay. And it didn't get anything wrong the other way in that it didn't call anything positive that wasn't actually positive. And that's very important because you don't want to be telling people to have COVID when they do not in fact have it.

Katie - So 98 to 99%, is that good enough? Can it be made better? Can it be made faster?

Ravi - Well, there's always a trade off here. The reason it takes 75 minutes is because you still have to amplify the stuff that's there in the first place. And that takes time. So if you're going to develop a highly sensitive test, you need to have time for amplification to occur. If you just use a standard antigen test, which is just looking for protein that cannot be amplified, your tests are much less sensitive in general. And so there is a, there is a trade off here and a cost to having accuracy. And that is time. And I think an hour is actually pretty good in terms of getting a test result. The biggest delays sometimes actually are getting the swab from the nose and throat and getting the sample to the machine. If we can cut that down, for example, using saliva, I think things could get even faster.

Katie - Why is speed so important when it comes to testing?

Ravi - Well, speed is of the essence because when a patient comes into hospital, we want to prevent any transmission within the hospital. And so we have to pick out those people with symptoms who may or may not have COVID. Of course, the problem is that the symptoms are very vague, ranging from runny nose to cough, to headaches, to problems with your sense of smell. So it's very difficult to tease out who has COVID and who doesn't. And therefore we need to have a rapid test that can give us that answer quickly because the clinical diagnosis is not particularly accurate and we need to isolate infected patients rapidly to prevent spread.

Katie - Ravi, it's July at the minute. But looking ahead to winter of 2020, there's all kinds of seasonal coughs, colds, bugs that come along with that time of year. How does this relate to testing for COVID? Does winter pose a threat?

Ravi - Yes, we're all somewhat concerned about winter here in the UK, because as we can see COVID has not gone away and we are relaxing certain measures, and therefore we expect the number of cases to rise. And this rise may indeed end up coinciding with the seasonal influenza epidemic. And it's probably going to be a smaller one this year because of social distancing worldwide, but it will still probably arrive. And of course, other cold viruses that circulate in winter. And the key thing here is that we need to design tests or have tests available that can test for multiple different viruses at the same time in order to differentiate patients and to treat them appropriately in terms of isolation. Of course, the most important virus of those three or four is going to be coronavirus even going into winter.

Katie - But we don't have those tests right now is that, is that right?

Ravi - So a number of individuals and companies are looking at things called multiplex tests, which are rapid tests often that can detect a number of different viruses at the same time. We know that the Samba machine is being adapted to do a number of different pathogens at the same time, but will require validation as we did for the single test in order to make sure that it's as good as it needs to be. And the same goes for all the commercial tests that are being developed that go on to much larger machines and can run much larger numbers of samples. Those will also need to be tested. And this is a bit of a challenge because of course, we're going into a period where we have declining numbers of cases and actually evaluating the tests in real patient samples becomes more difficult as the number of cases in hospitals decreases.

Blood samples being tested in a laboratory

Antibody testing for Covid-19
Chris Xu, Thermogenesis; Sara Lear and Anita Chandra, Addenbrooke's Hospital

What about the question of whether you've had the infection in the past? This is where tests for antibodies come in. If there are antibodies against an infection in the blood, it shows that a person has been exposed to that infection previously. As immunologist Chris Xu puts it, antibodies are a bit like the footprints an animal leaves behind. And by identifying those footprints, you can tell what animals have been in the neighbourhood. At his company Thermogenesis, he's invented a test kit that people can use at home...

Chris Xu - The test is very simple. It's attacking humans' immune response against the virus. It takes one droplet of blood, and we can read the result in about two to three minutes. The test we believe to be more than 90% accurate.

Chris - But that still means that you're potentially getting it wrong 10% of the time, doesn't it?

Chris Xu - Yes. Each test has its limitations. There are many different factors that could be affecting the performance of a test, such as viral mutations. If the virus mutated things then certainly it will not be recognized by the antibody tests. Or also the blood chemistry might interfere with the performance of the test.

Chris Xu sent Chris Smith some samples of his test so that we could try it against another kind of antibody test, this time one that can be run in a laboratory to test large numbers of patients quickly and accurately. It’s been developed by immunologists at Addenbrooke’s Hospital in Cambridge.  Chris Smith went to see Drs Sara Lear and Anita Chandra and asked them to tell him how their test works, and to put Chris Xu's test to the test using Anita’s own antibodies! But first Anita answered this crucial question..

Anita - An antibody is a protein that circulates in the blood or can be in various tissues of the body and its job is to help fight various forms of infections be they bacteria, viruses or parasites. There are many different forms, what we call classes of antibodies, and there are lots of antibodies against different bugs. So you can have antibodies against coronavirus, mumps, measles.

Chris - Where do they come from?

Anita - We have white cells that circulate in the blood and are made in our bone marrow that have the capacity to produce what we call IgM antibodies. So these are the first type of antibodies that are our first line of defense and they have the capacity to recognise millions of different organisms. On the first exposure to, for example, a virus like coronavirus, we would make an IgM antibody. And then at a later stage, we would make a different type of antibody called IgG antibody.

Chris - Why make two different types?

Anita - The IgM is produced immediately. It has different effects to other cells of the immune system. The IgG comes along later - it circulates in the blood, has a long half life up to three weeks and it can cross the placenta. And it's the IgG antibodies that we measure when we look at vaccine responses, for example.

Chris - And Sara, if you make two different types of antibody at two different times, does that mean you could use that as the basis of a test for whether someone's got something right now or had something previously?

Sara - Yes. The IgM comes first. It's pretty quick. Within 24 hours, it starts being built up, peaks at about three days. And then the IgG kicks in after that. So if you do a test right at the beginning, you can measure the IgM and you can tell that's more likely to be an acute infection. And then if it's not an IgM, but an IgG, you can say, well, this has happened sometime in the past and it's not recent.

Chris - That's one of the things you've done here at Addenbrooke's, you've managed to make a test that actually looks for the antibodies against this new coronavirus. How does it work?

Sara - So all these tests work with the same principle that we need to get the bits of the virus that we're looking for, and we have to fix them somewhere and expose them to the antibody in the patient's blood. And then we have to be able to see that antibody protein complex. So in this case, we took the viral proteins and we stuck them onto tiny microbeads. And then we incubate that with the patient's serum, they stick together if the antibodies are there. Shine lights at it, and if you've got an antibody antigen complex there, then it will shine up and give you a light measurement.

Chris - And it glows only if the antibodies are stuck on?

Sara - Exactly.

Chris - And it works?

Sara - Yes! Yes, it does work.

Chris - Now I got you here under slightly false pretences Anita, because Sara let it slip that actually you're a positive control in all her experiments, because you have antibodies. You have without realising it had coronavirus infection. So will you be a guinea pig for us?

Anita - Yes. I'm very happy to be your guinea pig.

Chris - Okay. I understand you are the lab guinea pig anyway. This is a point of care test, which has been sent to me from a laboratory in America. And the way it works is that we need a sample of blood from your finger, and it will register whether you have antibodies of the IgG or IgM type. You need to use this alcohol soaked swab to make it all clean.

Anita - Thank you.

Chris - You're now going to take that green thing, which is sprung loaded, and you hold that against your finger and it's going to put a little tiny blade into the skin and we should make a hole in you and some blood should start to come out. Press that. Are you alive?

Anita - I'm still alive!

Chris - Use the little pipette I've got here and just suck that drop of blood up off your finger. Blimey there's a lot coming out. There's a nice dry swab. This is the actual test cartridge. It's about the length of your finger. And it's about the width of your finger as well, isn't it. And there is one end which is a well where you put the sample. And then there is this area about a centimetre long and about two or three millimetres wide. That's where we're going to see your result. So what you have to do is take about five drops of your blood. Yep. Using the pipette and just drop it where it says S for the sample.

Anita - Here?

Chris - Yup. So in goes the sample. Now we just have to leave it to cook.

Anita - Okay. Is this like a little pregnancy test?

Chris - Yes, it does give lines. Just like pregnancy tests. There's a C there, which is the control one, which says it has worked. And then there are two or one line will come up for antibodies on there. We'll put that to one side and we'll see in a minute what the result is. Sara, do we feel we understand how we respond to coronavirus infection?

Sara - So I think no has to be the answer to that one. There are some features of this virus that appear very different and that are unusual. The antibody test will help, I think, to pick up how many people in the environment have been exposed to it, but we need to do more work around the acute infection to see how it actually evolves.

Chris - Do we have any feeling Anita for once you've made a response, whether that lasts very long or does it disappear?

Anita - That's what we're still trying to ascertain in the labs at the moment. I think a lot of that data from China will be very important because they are now at least six months in and they will be able to look at the patients and their convalescent samples to see how long they have antibodies and whether they are protected.

Chris - Why should the antibody disappear though? It seems a bit strange that for some infections you have antibody and you have it for life. Whereas with this one we're uncertain as to whether it will hang around for any appreciable time. Why might that be the case?

Anita - Some of the other SARS-like viruses, they found that the antibodies only last for two years, I don't know why it's only two years in this SARS-virus, whereas for some patients like the influenza virus, there are patients who are over a hundred and who were exposed in 1918, and they still have evidence of antibodies to the influence of virus. So for that, I'll have to raise my hands and say, I don't know.

Chris - What might the implications for a vaccine be then Sara?

Sara - Vaccines work in two ways and the antibody response is only part of that. There's also a cellular response, which forms a really important part of how you clear viruses from the system.

Chris - Cause researchers in Sweden this week have said that there are people knocking around who don't have appreciable antibodies, but they are sure as hell immune to this new virus. How might that be then?

Sara - When your body comes across a new virus, T cells come along and they recognise those proteins exposed on the cell surface as being foreign and that can induce a cellular response, which means that the cell that's infected gets destroyed. And the cells will be able to recognise that combination again in the future and will then protect you for longer term.

Chris - So you can have low levels of antibody, but because you've got these T cells that recognise a virally infected cell, that's going to give you protection as well. So it's not just a one prong, it's a two pronged response.

Sara - Yes. And there are other cells and neutrophils when exposed to coronavirus, they produce these little nets that capture them and eat them. The immune system is very complicated, which is why it's very, very interesting to study.

Chris - Well, look, I think on that note, it's moment of truth time isn't it. Should we have a look and see? So here is your result, Anita, and I see one very strong red line against the control showing that the test has worked, but come on immunologist, is there anything else on that line, on the IgG?

Sara - Yes, I think there's a faint line on the IgG. It's very faint.

Chris - Okay. With the eye of faith, there might be a very faint line where the IgG antibodies are. Have you had it Sara?

Sara - I haven't had the test.

Chris - Because you share an office with this woman.

Sara - So I'm safe, right?

Chris - Not initially, not potentially.

Sara - I haven't done it because I haven't been ill.

Anita - Out of curiosity, you haven't checked?

Chris - You wanna, do you want to do a test?

Sara - I don't trust that!

Chris - I don't like your test. It's not as good as mine.

Sara - I haven't got around to it!

Chris - Should we make her do one of these?

Anita - I think we should!

image of a stethoscope and a laptop computer

45:50 - Patches to monitor Covid symptoms

A plaster-like sensor to monitor Covid symptoms...

Patches to monitor Covid symptoms
John Rogers, Northwestern University

If you’re in hospital, recovering at home, or at work in a high risk environment like a hospital or care home, regular and frequent health monitoring can provide valuable information about how you’re doing regarding covid. Indeed, covid monitoring isn’t limited to the indoors. This week we heard news that monitoring sewage for covid could pick up infection spikes up to 10 days earlier than with medical-based tests. But, back in 2019, Northwestern University’s John Rogers told us about sensor technology he’s developing that can non-invasively collect information such as heart rhythm, body temperature and blood oxygenation. At the time, he had premature babies in mind. But now, he and his colleagues have redeployed the technology to help combat  covid. And in hospitals and homes around Chicago are 100 of these patches, which sit at the bottom of the neck and collect valuable health data about the wearer. John told Katie Haylor about it...

John - Well, they're wearable devices, you know, in the conventional sense of the term. But they're very unusual in their form factor. They're very thin, soft and flexible. They mount on the body just like a band-aid. And when positioned, kind of, at the base of the neck, they operate as a wireless digital stethoscope, is the way that you can think about it. And, you know, it's a device that continuously talks and streams data, to the cell phone. And from those kinds of measurements, you can determine respiratory behaviors and that's important because COVID-19 is essentially a respiratory disease. And so you can measure all sorts of body sounds just like you would with a stethoscope. So you can hear the lub-dub sound of the heart. You can also listen to air rushing into the lungs and during expiration, you can count coughs. You can measure intensity and sounds of coughs. We also have a temperature sensor embedded in the device, so we can pick up early signs of a fever as well.

Katie - How is it powered?

John - There's a tiny battery in the device and it operates the sensor itself. There's an onboard memory module, so we can store data locally. There's also a Bluetooth radio that allows that kind of continuous streaming mode to send data to a cell phone or a tablet.

Katie - How does this monitoring compare to if you had a human do it?

John - Well, it's measuring these quantities continuously, all the time and it's measuring parameters that would be difficult for a human from a practical standpoint to keep track of. It's doing heart rate, essentially, cardiac sounds is kind of the basis of the measurement. Respiratory rate, respiratory rate variability, core body temperature. We also have a module that allows for measurements of blood oxygen levels. And so I assume if you are a super diligent individual and you have a health diary, you could sort of track some of these parameters, but I don't think that's really practical. And in many cases, what we've seen in COVID patients that have had been wearing these devices is some of the key symptoms are very transitory in a timing sense. And so there are spikes in heart rate, for example. And so if you're not tracking and monitoring these parameters continuously, you sort of miss some of the key signs of the symptoms of the disease.

Katie - Is the idea that these would be used in hospitals, in the community, or a bit of both?

John - A bit of both. So we have about a hundred devices deployed in various areas of the medical complex here in Chicago. We were approached by physicians, doctors, pulmonologists, respiratory rehabilitation scientists, and so on in early April. And they were aware of a lot of our work in monitoring of neonatal health. And they asked us whether we could adopt that technology, adapt it and customise it to directly address the key symptoms of COVID-19, which are fever, shortness of breath and coughing. And so that really got us started down this path. And their vision, and one that we share is that these devices can monitor front-line healthcare workers or others who are at a high risk of contracting the disease.

So we can monitor very early signs of symptoms in those individuals, so that they can be pulled out of the community and care can be delivered to them at the earliest possible moment. But we're also on patients at various stages of the disease itself, both in the hospital and after they're released to the home setting. So we can track the progression of the disease. We can determine exactly how their condition is evolving, and how it's responding to the various novel therapies that are being addressed. So we can look at improvements. We can also look at deterioration of that health status. All the data goes to a secure cloud server, which presents the data in a sort of dashboard that physicians can inspect and base judgments on in terms of how to best treat and care for their patients.

 

A man using a smartphone.

50:49 - The future of digital contact tracing

Contact tracing: what if the UK app doesn't happen?

The future of digital contact tracing
Ramsey Farragher, Focal Point Positioning

So far in the show we’ve talked covid testing and monitoring. Now to tracking and tracing the infection. Last week, Germany launched what it claims is the world’s best app for covid contact tracing. We were expecting ours in May, but so far it’s failed to materialise. Last week we got the lowdown on this from University of Strathclyde security engineer Greig Paul...

Greig - They had an app, they were testing it on the Isle of Wight. And it started to hit some teething problems around iOS devices recognising each other. And the reason for this was Apple has some technical restrictions on how Bluetooth works on their devices, that they're not able to work around unless they go down Apple's approved route of contact tracing.

So what’s next? What if the app doesn’t happen? Where does digital contact tracing go from here? Ramsey Farragher is CEO of Cambridge company Focal Point Positioning, who specialise in navigation and positioning. Ramsey joined us on the show back in March with a proposal to use bluetooth for Covid contact tracing, and Chris caught up with him, firstly asking why the UK has struggled so much to get the contact tracing app off the ground...

Ramsey - The challenge that has come about with the UK contact tracing app was fundamentally that this unknown problem occurred, which was to do with the iPhones, basically being asleep when the Bluetooth signal was trying to wake them up. Instead of just turning that bit off, so that that wouldn't happen anymore, Apple and Google got together and created their own view of how contact tracing should be done. It prioritises battery life and it prioritises privacy. And that means they fundamentally change bits to do with how Bluetooth is used. And it does indeed turn out that the NHSX app was doing a better job of determining how close another device was than the Google and Apple system can do. And it's because of these priorities. And so people like me are sort of advising Apple and Google and others on changes they can make to make it a bit better. The simplest thing is to do with how often the devices try to talk to each other.

Chris - If I may, why do we have to use Bluetooth? This is a radio wave, isn't it, between two devices. And I put it to you that if you're sitting on one side of wall and I'm sitting on the other and Bluetooth goes through the wall, the device doesn't necessarily know there's a wall there, because radio sees a wall as transparent and goes straight through. Why can't we use some other way? Why can't we do it with sound for example, it's perfectly capable of making, we can make a dog whistle that my dog can hear and probably my children, but I can't. Why can't we make the phones, do this with sound?

Ramsey - We can, and people are starting to look into ultrasound for this. The reason we started with Bluetooth is because it's all set up already in the phone for them to talk to each other over Bluetooth. And you're right, the signal goes through walls and windows and glass, and that means you'll get more false positives. And so there are entities that are looking at building apps, using ultrasound instead, which at the moment is a bit of a hack. So it's using the speaker and the microphone in your phone to transmit an ultrasonic chirp that you won't hear, but the phones can pick up, and you can use that to detect the proximity of two phones to within a centimetre, which is much better than Bluetooth, which is about a metre in resolution.

Chris - That sounds quite promising. In Singapore, where they're conscious of the fact that not everybody has got a smartphone device, so not everyone's going to want to run one of these things, and there are these headaches with how Apple have decided to inflict themselves on the world, people are using other kinds of specialist devices. They've actually issued handheld contact tracing devices that do what they do want to do, without the constraints imposed by third parties. Do you think that might be a possible solution here?

Ramsey - Yeah, it's a really good idea. It gets around the challenges that we've seen with trying to do it directly on smartphones. And it means that vulnerable people who might not have a smartphone or might not remember to keep them charged, can be given a necklace or a bracelet that does the same job and does it with a very long battery life. Because it's dedicated for that role. So they're a good idea. And I think we'll see them over here.

Chris - Do you think that's going to be what we end up doing then? Or do you think we are going to get this mysterious app. Because Germany have done it. They reckon they've got the world's best app. They've got a problem with people wanting not to download it, but that's a different problem.

Ramsey - Well, independent tests of their apps suggest it's not quite as good as they're claiming, but I do know that the Apple/Google methodology is steadily improving, so it will get better and we'll get there in the end. And people like me are trying to make everyone get there as fast as we can.

 

 

A cup on its side, with coffee beans spilling out of it

56:01 - QotW: Why does coffee dissolve so fast?

What magic do coffee granules possess that's absent in packet soup?

QotW: Why does coffee dissolve so fast?

Adam Murphy poured over the answer with Cambridge University chemist Ljiljana Fruk...

Adam - Yeah, when you pour in that water, the instant coffee disappears, ready for that first sip

[SIPPING NOISE]

Ugh, I don’t like coffee.

Ljiljana - But, thankfully, University of Cambridge chemist Ljijana Fruk does, and knows how it dissolves so quickly

Ahhh.. that beautiful smell of coffee in the morning, and that caffeine kick  that helps us to get to that early morning zoom meeting. But sometimes, we just do not have time for the coffee to get brewed and we need some more  instant. Instant coffee!

And making a nicely soluble instant coffee required a bit of chemical engineering.

Coffee granules we dissolve in hot water are nothing else but brewed coffee, which was dehydrated: the water was removed either by process of spray- or freeze drying. These processes result in fine powder, which is not particularly soluble: it binds the water and clumps, and  it doesn't really look nice. And it also doesn't dissolve readily. 

Adam - That means you need to do something to those particles to make them dissolve so quickly, but what could possibly jump in here?

Ljiljana - Enter granulation: a process by which fine powder particles are made larger, they agglomerate into bigger and more porous particles which have larger surface and are easier for the water to flow. There is a size, which is considered very good in terms of solubility of granules,  and this is usually around 250 micrometers. 

Adam - That explains coffee, but what about instant soup. Which I do like.

Ljiljana Soup is a bit different. It contains many different ingredients. All of these: many ingredients with different properties, use of binders, presence of starch makes uniform granulation more difficult, and results in instant soup that requires hot water and mechanical mixing to dissolve, unlike our homogeneous and granulated instant coffee

Adam - Thanks to Ljiljana for that solution. Next week, we’ll be answering this question, from Carol

Carol - The government has provided  more than a billion items of PPE to hospitals. There have been 130,000 covid cases in hospitals, about 10,000 items of PPE per patient. Can you find out why so much?

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