Where Did COVID Come From?

We've unpacked the evidence - and the gaps in the evidence - surrounding the origin of the coronavirus.....
01 September 2020
Presented by Chris Smith, Phil Sansom
Production by Phil Sansom.

BAT_CORONAVIRUS

A bat hanging from a wooden beam surrounded by green coronavirus particles.

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Where did the coronavirus come from? The story we've been told is that it started off in bats, and then jumped into humans some time late last year at a seafood market in the city of Wuhan. It’s a neat tale - but the problem is, nobody actually knows whether it’s completely accurate. In this programme, we're exploring the possibilities, the evidence, and the gaps in the evidence...

In this episode

The logo of the World Health Organisation.

00:48 - WHO plans mission to China

The advance party has been and gone - and now an international team will travel to Wuhan to ask questions...

WHO plans mission to China
Tedros Ghebreyesus & Michael Ryan, WHO

The story we've been told is that the coronavirus came from bats and jumped into humans some time late last year at a seafood market in the city of Wuhan, China. It’s a neat tale - but the problem is, nobody actually knows whether it’s true, and the evidence is mixed. Which is why the WHO’s Director-General Tedros Ghebreyesus, speaking in July, said...

Tedros - Over the past few months, there has been a lot of discussion about the origins of COVID-19. All preparations have been finalised and WHO experts will be traveling to China this weekend, to prepare scientific plans with their Chinese counterparts, for identifying the zoonotic sources of the disease.

The two people the WHO sent were just the advance party for a much bigger group of scientists leaving soon for Wuhan, to start asking hard questions. From the WHO, Michael Ryan...

Michael - The answers to these questions are sometimes elusive, and it is quite a detective story to find the source, and the intermediate pathways by which the virus can breach that barrier to humans. We spent decades trying to do that in ebola. We spent years trying to do that with MERS and SARS. It takes time. And it does take a meticulous, multi-sectoral approach to this. And we don't know where that species barrier was actually breached. This is very important because unless we understand... like anything, if the walls of your castle are breached, you need to know where the breach is because you can fix and repair that breach. You can make sure that that is strengthened for the future. So we need to understand: what was the track of this virus? From the wild animal kingdom directly into humans? Directly through farmed animals? Directly into a market, one market, two, how many? We have to keep an open mind. Science must stay open to all possibilities.

A colony of bats in the air.

03:45 - Why COVID was first linked to bats

The first cases were reported in people in the city of Wuhan. Where and how did bats get involved?

Why COVID was first linked to bats
Dennis Carroll, Global Virome Project

On the very last day of 2019, China reported an outbreak of a strange pneumonia in a cluster of people with links to the local Huanan live animal and seafood market. Two weeks later, the cause of the illness was identified as a new coronavirus, now named SARS-CoV-2, that causes the syndrome known as COVID-19. Since then, thousands of scientific papers have been published on the outbreak, including the genetic sequence of the new virus, which confirms its close relationship to coronaviruses carried by bats and therefore gives us clues of where this new coronavirus came from. Dennis Carroll heads the Global Virome Project, and explained to Chris Smith...

Dennis - The coronaviruses first and foremost are a family of viruses. We estimate there are between 4,000 - 5,000 different coronaviruses, and virtually all of the ones that we've discovered to date, about 200, we found in bats in different parts of the world; Asia, Africa, and in the Americas.

Chris - And why bats?

Dennis - We don't know why bats, except that bats are able to host viruses like coronavirus without themselves having any adverse effects, and they will periodically shed these viruses in their faeces or in their saliva. So they represent sort of an ideal host, because a virus... when it does infect another animal, the last thing it wants to do is to kill that animal off, it speaks to its own demise as well. So they've developed a very sympathetic relationship with bats over the millenia.

Chris - Are you saying that bats are the origin, and when you get coronaviruses in other species, it represents a jump from a bat into that species, at least at some point in time?

Dennis - Well first let's be very clear. We don't have a definitive answer as to how the COVID-19 virus entered the human population, but we've seen enough examples of the virus moving, either directly or indirectly, from bats, that it's the most reasonable explanation. There was some initial speculation, to be confirmed, that pangolin, another wildlife animal that is a food source in China, may have acted as a spillover agent; but more work needs to be done to really clarify exactly what the transmission route might've been.

Chris - One other avenue to pursue is: you read the genetic code of a virus, and then you go looking in the database to see what it's most closely related to, because that can sometimes point you in the right direction of where something came from. What story emerges when we do that sort of analysis?

Dennis - Many of the different coronaviruses circulating in these geographic areas do in fact have a strong genetic relatedness to the COVID-19 genetic profile. So it speaks to a pedigree, a shared pedigree.

Chris - If that's the case then, and you're making a case of the fact that these viruses are actually pretty common - you can find them across a very diverse patch of China - why would they emerge in Wuhan?

Dennis - Well the source is largely bats that are proximal to Wuhan City. And one of the things we know about bats first and foremost is that they have the ability to adapt and share a living space with human populations. What we've seen in Wuhan is an example of high interactive dynamics between bat populations; possibly, again, secondary intermediary hosts with human populations. If we don't bring a human in close proximity to these infected animals, you will not get a spillover.

Chris - So if that virus is present in Wuhan in the bat population there in the way that you're suggesting, surely the Chinese have already done sampling of the bats in Wuhan to try to find out if that's the case. If so, where is it then?

Dennis - Well let's first off acknowledge: going out and collecting bats, identifying viruses, is a very complicated exercise. So right now there isn't direct capture of a COVID-19 virus from a bat. But at some point it's inevitable that we will find it.

Face masks

08:33 - SARS from horseshoe bats: history repeating itself?

Hearing about the new coronavirus, many were struck with déjà vu - because parts have happened before...

SARS from horseshoe bats: history repeating itself?
Peter Daszak, EcoHealth Alliance

As the story about the new coronavirus was coming out, many were struck by a sense of déjà vu. Because this has happened before, in 2002, with an epidemic caused by another coronavirus: the one that caused the original SARS, or “severe acute respiratory syndrome”. Disease ecologist Peter Daszak worked to try and curb the spread of these two viruses that came two decades apart. The new coronavirus is genetically quite similar to SARS, and there’s a lot we can learn from exploring the past here, because as he told Phil Sansom, that is far from the only similarity…

Peter - The original SARS outbreak began in south China, Guangdong province, where there are some really large cities, like the city of Guangzhou with very big wildlife markets. People in South China have a tradition of eating wildlife. It's very strong and still continues. And they have really large markets that bring incredible diversity of animals together. And these animals can be in the wildlife trade for weeks; so they're swapping viruses around between each other, they're picking up new viruses; and then when they get to the market, there are thousands of people that go in and out of these markets. And SARS, the original SARS outbreak, began in a wildlife market. It was very clear. The first cases were related. And we started working there at the end of the outbreak to say, well, if the market is where it began, which animal did it come from, and where in China was that animal first caught, because the virus could still be out there.

Phil - What did you find?

Peter - At the time, people were saying that civets, these small ferret- or badger-like animals, were the source of the virus; and what we found was that's not really the case, that bats are the real reservoirs, they're the animals that carry these viruses, and have done probably for millions of years in the wild. And then the virus got into other species of animals in the markets, in the wildlife trade, and then got into people. So we traced the virus back to rural China. And we ended up in Yunnan province, which is a really beautiful part of southwest China which has a lot of wildlife diversity, a lot of intact countryside. And it looks like they were picked up by people hunting bats and bringing them into markets, and the virus spread then through the trade.

Phil - That certainly sounds a lot like SARS-CoV-2, because we really think that came originally from bats, don't we?

Peter - Yeah, without a doubt, it's pretty clear that bats are the origin. Every relative of the whole SARS group of viruses is found in bats, and the closest known relatives to SARS-CoV-2 are from bats as well.

A sleeping bat.

11:30 - How did the coronavirus get from bats to us?

Scientists haven't found an animal carrying the coronavirus yet. Where is it? And is it a bat or not?

How did the coronavirus get from bats to us?
Raina Plowright, Montana State University

It seems extremely likely that bats were the ‘reservoir’ for COVID. But what we don’t know is how it got from them into us, because scientists haven’t yet found an animal that’s actually currently carrying the new coronavirus. Disease ecologist Raina Plowright told Phil Sansom where that animal might be - and how it might have transmitted the virus to humans...

Raina - This virus hasn't actually been sampled in bats. And that's fair, because it would take sampling thousands and thousands of bats to find every single coronavirus that is in existence. But we know that viruses - similar viruses - circulate in horseshoe bats. We know that they circulate in the area of southeast Asia, and southern China, and northern Vietnam, Myanmar, Laos. And so perhaps the virus came from that region. Did it come within a bat to Wuhan, or did it come within a human? We don't know. One of the challenges with coronaviruses is that of the three coronaviruses that have spilled over from animals to people in the last 20 years, each of those potentially has spilled into the human population through a single event. And then for this pathogen, the circumstances are still a mystery, but perhaps it was a single event from a bat, either into a human or into a bridging host. We've talked about pangolins as a potential bridging host; civets, ferrets; we know that felines are actually very susceptible as well.

Phil - Is there any way of telling whether there was a species in the middle, or if it went straight from bats to humans?

Raina - We don't know at this point. But one of the really critical questions is: was the virus supercritical in bats? What I mean by supercritical is that when it infects a human, that human can not only be infected, but that human can then infect others at a rate that's high enough to sustain a chain of transmission. And earlier on we thought that perhaps in bats, the virus wasn't in a form where it could just take off and spread in humans; that it needed a little bit of a genetic mix-up, and that maybe that mix up happened in another species. But more recent evidence is seeming to suggest that, actually, these may be supercritical already in bats; it's just that we haven't sampled the right bat to find the right pathogen. But I do think that we could still try to understand this event by going into the regions where we know the similar viruses occur, the southern area of China and that area of northern Vietnam, Laos, Myanmar; and looking at people, and then trying to do the serological surveys, looking for exposure to other coronaviruses, trying to understand how spillover occurs from animals to people.

Phil - Is that kind of what a spillover means?

Raina - We often think of spillover as this simple jump, and I think because we often don't see it we think of it very simplistically. But when you start to deconstruct all of the things that have to happen for spillover to occur, it's very, very complicated, and it's really quite extraordinary that it occurs at all. And I think it is actually very rare. So if you think about it, every time you leave your house - which isn't that often these days, right - but when we do, we're breathing the air; and that air is full of microbes, but we don't often get sick. So a whole bunch of things have to align: you have to have the reservoir host, that host has to be infected, that virus has to get out of the reservoir host - for example, coronaviruses are shed in the faeces of bats - often the virus has to survive in the environment for some time, and then it gets really complicated because then the virus has to go through a whole bunch of barriers within us to allow it to infect our cells, to replicate in the cells, to be able to exit the cells, disseminate through our body. It has to be able to overcome our innate immune system. And then it's got to be able to exit us, it's got to be able to be transmitted to the next person. Because it's somewhat rare for all of those things to line up at one point in space and time, spillover is a relatively rare phenomenon.

Rats leaning over the edge of their container.

15:48 - Coronavirus risk increases up the wildlife supply chain

In the live rodent trade, infections with a coronavirus go up the closer you get to the consumer...

Coronavirus risk increases up the wildlife supply chain
Amanda Fine, Wildlife Conservation Society

There are a few ways that viruses can jump from animals into humans. But the wildlife trade is still a prime suspect, because as wild animals are caught, shipped along to cities, and served at markets or restaurants, there are a huge number of opportunities for people to catch a coronavirus off the raw meat. And now, scientists at the Wildlife Conservation Society have shown that as you move along this supply chain, the number of animals infected with coronaviruses goes up, increasing the risk for humans as well. Eva Higginbotham spoke with lead researcher Amanda Fine...

Amanda - We looked at the live rodent trade - rodents that are collected by traders then moving through to large markets and to restaurants - to look at the prevalence and also the diversity of coronaviruses. We found significant differences. with traders, trackers, we had about 18% of those samples we tested were positive; and then as we got to large markets where you're bringing in animals from a lot of different sources, we were up to 32.8%. And then at the end consumer, primarily in restaurants, we had just over 50% were positive. What we're seeing is the result of animals with their coronaviruses coming from many different places, mixing, transmission occurring. Many of those animals in the trade chain are stressed and therefore more susceptible to virus, and potentially would shed more virus. As they go further to the end consumer, they're meeting more animals from different populations, and you get more transmission and therefore more samples that are positive when you test.

Eva - So the number of animals that have coronavirus goes up, but what about people?

Amanda - We would expect that the risk of one of those viruses moving from the wildlife to the people, the more there are, the higher the risk. How a human would become infected with a virus very much depends on the kind of contact they have. The more contact you have, the more potential there is for transmission; so definitely handling exposure to the virus in the environment, and direct contact through consumption of the wildlife as well.

Eva - Does that also increase the risk for making a virus that is going to be more of a problem for humans, because you have more mixing of more viruses, in more animals, in close proximity?

Amanda - We definitely think so. In this study, we show that you have an increase in the overall number of these coronaviruses, that is more opportunity for different individual viruses to recombine in an individual or for those to recombine and affect another. So that is the process through which a new virus emerges.

Eva - So it's kind of like a perfect storm for speeding up evolution of these viruses, in a way.

Amanda - Absolutely.

A view of low clouds and mountain ranges in China's Yunnan province.

20:12 - Genetic tree suggests origin in rural China

Based on the first gene sequences of the coronavirus, it may not have come from Wuhan at all...

Genetic tree suggests origin in rural China
Peter Forster, University of Cambridge

Wuhan, where the pandemic was first picked up, is a city in the Chinese province of Hubei, which is roughly in the centre of the country. Peter Daszak mentioned earlier two provinces that are in the very south: Guangdong, which is where SARS 1 made the leap into humans; and Yunnan, a rural province where the bats carrying SARS 1 originally came from. These are notable - Guangdong and Yunnan - for reasons that Peter explains...

Peter - For COVID, the wildlife market seems to have been a place where there were lots of people spreading the virus. It doesn't look like that was the actual origin of the virus. It seems that there were some patients that didn't have contact with the market, and they were the first few to be identified. So it looks like it came from somewhere else, it got into the market system, and then spread rapidly in people.

We’ve known since January that the first reported COVID case had no link to the market, and neither did a dozen cases from the initial batch. So if the jump into humans did not happen there - then where? Evidence from the genetic sequence of viruses sampled early in the outbreak indicates that it may not have been Wuhan at all, as Cambridge University’s Peter Forster told Phil Sansom…

Peter - We analysed the first 160 coronavirus genomes, taken mainly from patients in East Asia, but also from the first patients in the Western world, so Australia, Europe, North America. And we applied what we call a network algorithm to reconstruct how the viruses are related to each other; it's like a family tree. And we found at the beginning of March, there were three main types of viruses. We call them A, B and C. And we compared these A/B/C types with the bat coronavirus, which clearly showed that the A type was the ancestral type. And that was a surprise because the A type is not common in the Chinese city of Wuhan. It's the B type that is most common there. Up to then, I had believed that the virus had come from the fish market in Wuhan. And somehow that didn't seem compatible with our analysis.

Phil - I thought there was only one coronavirus though. What do you mean there's A, B and C?

Peter - These viruses mutate all the time, they change. A, B and C differ from each other by mutations: A differs from B by two mutations, which changes an amino acid so the virus now looks slightly different; B has mutated into C by another amino acid change, so the virus, again, it looks a bit different. In the course of March, we've had a quite amazing development: a B subtype, which was about 3% of our sample in early March, now has become the dominant type across the world.

Phil - Then if you get this B type of coronavirus, do you get sick in a different way compared to if you had the original A type, for example?

Peter - An American group looked at a hundred patients who have this new B subtype, which has become dominant, and another a hundred patients who have other coronavirus types. And they saw no major clinical differences. But what they did see was those patients with the new B subtype, they have a higher viral load. And it is immediately obvious then if you have more virus and then you cough and sneeze, you can infect people more easily and therefore this virus type will become dominant. And that is what seems to have happened.

Phil - What does your tree, then, tell you about when these different strains evolve, basically?

Peter - Roughly every two weeks, the virus undergoes one mutation. And if we take a look at how many mutations there are in our reconstructed network of viruses, we can see the ancestral virus started spreading between the 13th of September and the 7th of December. That is what we call the 95% confidence interval.

Phil - That's months before the first reported case.

Peter - Well, I don't think so to be honest, because the first reported case published in the Lancet in January was a patient who fell ill on 1st of December. So that means this patient must have been infected at the end of November. And that is precisely what our time estimate says. There are scientists who have calculated a beginning of the disease in December, mid December or so, but this has because they don't have these network algorithms to calculate accurately where the root type is, how fast the virus is mutating and so forth. But we're talking here about differences of only weeks.

Phil - Okay, that's the when. What about the where? Because you said you were skeptical about wet market theory in Wuhan city...

Peter - I think our results have made me skeptical about Wuhan fish market theory, especially since the first patient diagnosed had no contact with the fish market. Now you may know in January, there was the Chinese New Year's festival - the Chinese celebrate New Year - and people travel. So I decided, "well, let's make a cutoff date for the middle of January and let's see where the A types occur". And for this very early period, we have 23 virus genomes in Wuhan and only three of them are A types. The other 20 are B types. Whereas in other parts of China, you have more A types. So for example, in Guangdong, in Southern China, you have about 50% A types. You have an A type in Yunnan province. These are areas where the bat populations are. And therefore, I think if someone twists my arm and says, where did this virus come from? I think it's slightly more likely it came from the Southern provinces than from Wuhan.

Phil - How sure are you Peter?

Peter - Not sure at all for the origin, because we have such small sample sizes. I mean, I've told you there are 40 genomes available for the period between Christmas and mid January. You can hardly do statistics on such a very small sample size. So I'm not sure.

A rice field in Yunnan province, China.

26:38 - Disease spillovers: "a common occurrence"

Scientists tested people in rural China and found infections of a separate coronavirus...

Disease spillovers: "a common occurrence"
Maureen Miller, Columbia University

If the coronavirus did first get into humans somewhere far south of Wuhan, why did no one notice? One possible answer is that these spillovers from animals to humans are more common than you might think, and often difficult to detect. Maureen Miller from Columbia University worked with Zhengli Shi, from the Wuhan Institute of Virology, to test people in rural China for an entirely different coronavirus - as Phil Sansom heard…

Maureen - We went to a place in Yunnan where she had found a bat that could cause potential harm to humans. And what we found was that 3% of the population that lived near the bats that were infected with these coronaviruses, had already been infected. So spillover is quite a common occurrence.

Phil - This isn't the coronavirus that's caused the pandemic; this is just a random other one?

Maureen - It is a separate coronavirus, it is not close at all. There are many, many coronaviruses that bats carry. Only 1% of them are estimated to cause any kind of disease in humans. And what had been believed prior to this was that it always had to go through a secondary animal and then get transmitted to humans. Zhengli Shi was the first person to discover that bat coronaviruses could be potentially transmitted directly to humans; and we were able to prove that yes, indeed, that was so.

Phil - Why on earth did you suspect it might infect humans then?

Maureen - That is the work that Zhengli Shi does. She has collected genetic sequences for various coronaviruses that bats carry. This particular one had a spike that is able to directly infect humans.

Phil - And who did you go out and test?

Maureen - This was Yunnan province. And we just tested all kinds of community members: farmers, foresters, hunters. And when we found 3% positivity, there was no particular demographic profile that had higher risk. Because we know in general, hunters have a higher risk - they kill the animals, the animals can scratch them - but they were no higher risk than anybody else in that community.

Phil - How is that possible?

Maureen - Exactly! So bats are really everywhere. They often live in the roofs of houses. People go into caves where bats live to collect bat guano, because it is a very valued fertiliser for crops. There's all kinds of mechanisms of exposure, and bats are fairly revered in China, so everybody knows where they are and respects them and thinks nothing of them.

Phil - Is that not kind of scary? I mean, in Yunnan province, why wasn't there a pandemic that began?

Maureen - With this particular coronavirus, it appears to not have caused noteworthy disease. In COVID-19, many of the cases were asymptomatic; so we wouldn't notice that anyone was infected, because everyone feels fine. When we start to notice it is when there is an increase in deaths, particularly among the elderly, from pneumonia; but pneumonia is a leading cause of death among the elderly, particularly in rural areas. So people may not have noticed that there were excess deaths.

Phil - Is the implication that the new coronavirus started like this?

Maureen - Absolutely. Spillover is much more prevalent than we think it is. What's different about COVID-19 is that it spreads human to human. A lot of zoonotic disease spillover spreads from the animal directly to the human, and then the human does not transmit it to another human. When it becomes dangerous is when it mutates and then can become transmissible from human to human.

The Parrot Island Bridge over the Yangtze River in Wuhan City, China.

32:45 - COVID was already adapted to humans in Wuhan

Analysis of the very first SARS-CoV-2 samples shows they already looked evolved to infect us...

COVID was already adapted to humans in Wuhan
Alina Chan, Broad Institute; Shing Zhan, University of British Columbia

Part of the reason the coronavirus has been so successful - apart from the fact that more than half of cases may be asymptomatic - is that it’s also very good at infecting us, so it spreads very efficiently. And that’s been true since the very first recorded cases in Wuhan. Alina Chan from the Broad Institute and Shing Zhan from the University of British Columbia have analysed the genetic sequences from some of the first samples collected, and compared them. They then compared that variation to the first SARS, and spotted something odd. Phil Sansom asked them what...

Alina - SARS-2 is much more similar to SARS-1 in the late phase of its epidemic. In the case of SARS-1, when it first crossed from animals into humans we could see that the virus underwent adaptation to the new host, which was humans. And this was in the early phase of the epidemic; the virus was mutating, finding adaptive mutations that could help it transmit amongst humans. But by the time it hit the late phase of the epidemic, this genetic diversity was greatly reduced. So this finding suggested that by the time we detected SARS-2 in December of 2019, it was already really optimised, or highly adept at human transmission. So we are missing this whole period where SARS-2 should have been rapidly adapting to its new host, and this raises really important questions about where did SARS-2 come from.

Phil - Shing, could you please explain genetically what it means here for the SARS-2 to be similar to the late version of SARS-1, rather than the early one? What does genetic similarity mean here?

Shing - Within roughly the first three months of each outbreak, the genome of SARS-CoV-2 had about one fourth the amount of genetic diversity that was found in SARS-CoV-1. And we did have genetic sequence data for four samples in the Wuhan night seafood market, and we compared the genome sequences recovered from those samples to the genome sequence of the Wuhan reference of SARS-CoV-2; and what we found was that they're very similar. And what that led us to think was, maybe the outbreak that was happening at the market didn't start from some nonhuman intermediate host, but instead it could have come from some people who were already infected at the time and they were doing some grocery shopping at the market.

Phil - Where were these samples actually from? Were they from bits of meat or something?

Shing - The samples were, for example, doorknobs; they had even some samples from the sewers; and they have samples from the surfaces of garbage trucks. What it looked like to us was that the sequences were just very similar to that from humans. So there was no real evidence that data that the virus came from some animal sold at the market.

Phil - Alina, was this surprising to you?

Alina - Yeah, so in the case of SARS-1, they went straight to the local market and there they found numerous species of animals that carry SARS-1-like viruses. But importantly the SARS-1-like viruses were not a hundred percent match, and that's why we're surprised here. Here in SARS-2, when you look at the samples from the market, they're all nearly virtually 100% identical to the human version. And so what that suggests is that these viruses were not from animals that were the source of the virus, but rather that they had been dropped by humans who were infected and had visited the market.

Phil - In that case, where did this actually come from then?

Alina - There are three different scenarios that are plausible. One of them is: SARS-2 would have crossed from an animal into humans a long time ago - this could be months to years - and it just circulated undetected in the human population for that amount of time, picking up adaptive mutations along the way, and then it finally broke out in Wuhan once it had reached the state of high adaptation to human transmission. The second scenario: that SARS-2 was already pre-adapted for humans while in bats on intermediate host. And the last scenario, which is the most controversial, is that SARS-2 could have resulted from lab-based scenarios. And we're not saying this to accuse anyone of malicious intent; lab accidents happen frequently. Even the first SARS has escaped from many world-class labs, multiple times. Sometimes lab accidents happen.

A rustic key partly turned in a lock on a door.

37:09 - SARS-CoV-2: natural or man-made?

The virus binds perfectly to human proteins. What's the explanation?

SARS-CoV-2: natural or man-made?
Nik Petrovsky, Flinders University

Nik Petrovsky from Flinders University in Australia has been doing computer modelling of part of the surface coat of the virus - a region called the spike protein - that it uses to attach to human cells. He's also been modelling the corresponding human structure - called “ACE2” - that the spike binds to. Other animals have their own versions of ACE2 as well, but Nik’s work shows that the spike protein is much weaker at attaching to the animal versions than the human form - and he’s willing to speculate to Chris Smith about whether this is a hint the virus is manmade...

Nik - We use computer simulations which are very similar to computer programs that predict the weather, and they simulate each individual atom within a protein. And we can then use those to actually simulate the ACE2 from thirteen different species, ranging from bats to pangolins, to humans, to cats and dogs. The spike protein was predicted by our simulations to be the perfect key for the human ACE2, but not for the ACE2 from the other species; suggesting that humans were the original host.

Chris - Obviously that can't be entirely true, in the sense that this is a new virus which has obviously come from somewhere; humans don't just invent viruses in their own bodies. So where did it come from then?

Nik - One possibility that was put forward is that the virus has been circulating in humans in China, unknown, for many years. But typically we would know about that; people would be getting sick. And so then we have to look for other questions. Either it was a very rare chance event, or maybe it was designed specifically to be able to bind to human cells and infect them.

Chris - What about if we just explore the animals for a minute, because all throughout this story we've heard various suggestions: people saying it started as a bat virus, it in some way mixed with a pangolin virus and produced this perfect storm for humans. Is that not the most likely scenario here: that it's a mix and match virus that's got a few bits and pieces from various places, and by the time we're now studying it, it's just had enough time to optimise itself so it looks like a perfect fit for humans.

Nik - Well certainly that's possible, but if that was true, the virus itself and its ancestor should be able to be found in whatever animal that virus was created. In fact, the closest relative that's been found is a bat virus, which has about 96-97% similarity. Just to orientate you, the similarity between the genes in a mouse and a human is 99%. So it's definitely not a perfect match. But there's also part of the spike protein we were talking about, which is very critical to binding human cells, is actually more closely related to a pangolin coronavirus spike protein than it is to the bat. And that's where this idea... That COVID-19 had a father that was a bat virus and a mother that was a pangolin virus, and that's how it came about, as the progeny. That's certainly possible, but then we should expect to find the progeny in pangolins, which we haven't.

Chris - If it didn't then happen in a bat or a pangolin, how did it happen?

Nik - One hypothesis we haven't discussed so far is that this happened in a laboratory, where scientists routinely culture viruses and grow them. And so it's possible that you could get, if in a laboratory you were growing some bat viruses in one test tube and you were growing some pangolin viruses in another test tube, and they accidentally got mixed up in the presence of human cells, then you could create something like COVID-19 quite accidentally, even without deliberately intending to do that.

Chris - And if you did intend to do it deliberately?

Nik - We do know in some laboratories there is research going on that's called 'gain of function' research, where you deliberately try to genetically modify viruses to make them a lot more lethal, and in particular to make them more infectious to humans. And this is done to really try and predict what might be the next pandemic virus. And of course that creates enormous issues about, should you be creating a potential monster, or are you better to just wait until nature does it, and then respond to it?

Chris - And is there a smoking gun here then, that that may have happened?

Nik - We can't exclude the possibility that had happened. There's nothing scientifically that says this definitely didn't happen. We haven't yet found that wild COVID-19 ancestor, but if it was found, that would essentially say, yes, it was out there in wild animals and it crossed to humans. In terms of the laboratory hypothesis, essentially it would require an investigation of the most likely laboratories. Neither of these things are easy to do, of course.

A masked scientist uses a pipette to draw up blue liquid from a petri dish.

43:15 - The case against COVID coming from a lab

We can't rule out the possibility - but the evidence seems to point to a natural origin...

The case against COVID coming from a lab
David Robertson, University of Glasgow

We can’t rule out the possibility that the new coronavirus came from a lab. As we heard earlier, the closest known bat virus is 96% similar to the COVID19 virus, but that 4% difference is a big genetic sticking point. The new coronavirus also has an additional piece of genetic material in its spike protein; this is called a furin cleavage site and it makes the new virus much better adapted to spreading among humans. So is this by human design? Virologists like David Robertson from the University of Glasgow, here talking to Chris Smith, nevertheless say “no”...

David - When we compare the new human virus to the closest bat virus, it's about 4% different. That's relatively genetically close, but in terms of time, that represents many decades. And so that's telling us that the last shared ancestor was some considerable time ago. What this is telling us is there are circulating viruses, probably in bats, that we haven't sampled yet, that gave rise to this new human virus.

Chris - Surely though, if that ancestor for this SARS COV-2 which is causing the pandemic was frequent enough in its population to jump into people, why have we not found it then?

David - To directly answer that we can't be sure how frequent it is. It could have been a one-off, or a very small population of bat viruses that accidentally or incidentally got into humans; or alternatively we just haven't sampled well enough. There is a quite extensive lineage of viruses in the bat that just hasn't been sampled.

Chris: - Your hypothesis then would be, if we were to hunt carefully enough, we might find a species - probably a bat - that's harbouring the more direct ancestor of what is COVID?

David - Yes almost certainly, I think that's what all the data's pointing towards.

Chris - Along the way though, David, there've been interesting sort of spinoffs of this, where initially people tried to implicate snakes as being part of the equation; and then attention focused on these scaly mammals, the pangolins. How do these other species fit into this picture, then?

David - Well, some of them are just really poor analysis and the misinterpretation of some of the signals in the data. But the pangolins - we have recovered viruses that are close to the human virus. But it's not that the virus in the animal reservoir has adapted to humans per se, it's that it's a bit of a generalist and that's allowed it then to jump to several species.

Chris - People have mentioned that the spike on the outer coat of the virus has some special characteristics that, they're arguing, set it apart or make it stand out. What are they getting at?

David - The main one is there's a furin cleavage site in the spike protein, and that's a little bit of additional sequence. And that's unique to the SARS COV-2 lineage. There's no animal equivalent of that sequence. But what we do know is that because these viruses can generate hybrids, they what we call 'recombine', and that's probably what's happened in this case.

Chris - Does that furin cleavage site make a difference to the way the virus behaves, then?

David - We believe it's increasing the ability of the virus to bind to the human receptor, making it much more transmissible.

Chris - Is there a possibility then, based on the uniqueness of their structure and how effective it is, that this is the work of human hands - nature didn't endow us with this?

David - I would say it's very unlikely, because so many of the properties of this new virus we just didn't know about. We just didn't know what the closest relative viruses were. We still don't know. For a human to engineer a virus that's so unique and complicated, and in unexpected ways... it's just very unlikely. If you were to engineer a virus, you would have started with the first SARS virus and you would work from there. You wouldn't invent some novel virus with parts that we'd never seen before. It just seems very implausible.

Chris - What about if it was an accident? As in, someone's working on different coronaviruses and they just by chance happen to mix them up, and as you've said, they very often trade bits of genetic information between themselves. Could they not disclose this because it's so good at what it does, it would just naturally pop out and outgrow all the others and off it goes?

David - Well, I think first the overwhelming evidence is that these events can occur naturally. And so if you discover that you have viruses that are in reservoirs, that can transmit to humans, they have all the parts quite naturally. I think that's where the weight of the scientific evidence points towards.

The missing person at the centre of this story is Zhengli Shi, director of the Center for Emerging Infectious Diseases at the Wuhan Institute of Virology, nicknamed ‘batwoman’ in the Chinese press. A lot of what we know about these bat coronaviruses comes from research from her centre - and, as might be expected, claims that the new coronavirus escaped from a lab generally involve her as well, not least because many of the coronaviruses that are closely related to SARS-CoV-2 were discovered and worked on there by Shi and her team. Shi has said on the record that she “never expected this kind of thing to happen in Wuhan, in central China,” but that the allegation that the virus came from her lab, quote “totally contradicts the facts”. We can’t get in touch with her at the moment - very few can - but Maureen Miller from Columbia University worked with her, and has an idea what she might say…

Maureen - Well, first I don't want to put words in her mouth, but I do understand how frustrating it must be to have spent an entire career trying to prevent exactly the same kind of scenario that we're seeing right now, and people not heeding warnings, people not conducting more studies like we did in Yunnan province, where we found a bat that had a virus that could cause disease in humans. We have the technology to be able to do that. We know the global hotspots. We could be surveilling those areas.

A deforested clearing cut down for timber.

49:59 - SARS 3: how to plan for the next pandemic

When it comes to the origins of COVID, there are still lots of unknowns. But we can be sure of a sequel...

SARS 3: how to plan for the next pandemic
Peter Daszak, EcoHealth Alliance; Dennis Carroll, Global Virome Project; Raina Plowright, Montana State University

If you've heard one phrase more than any other in this programme, it’s “we don’t know”. We can make guesses, and gather evidence and hypothesise; but until someone finds the ancestor to this coronavirus, it’s going to remain a dangling question mark. That said, there are a few things scientists like Peter Daszak do know: that if we’ve had SARS 1 and SARS 2, you can bet there will be more...

Peter - I don't think ‘if’ we had a SARS-3, I think ‘when’ we'll have a SARS-3. There are hundreds of these viruses out there. People are increasingly well-connected on the planet. Every day these viruses are finding it easier to get into people and spread around the world. So we will have another one, but whether we're going to be better prepared... I really hope so, but I'm not confident that we'll learn our lesson. We haven't so far.

Phil - Could this have only happened here, in this part of the world - Southeast Asia?

Peter - Oh, well we know diseases emerge in just about all countries. We've had our own in the UK with BSE, mad cow disease, and salmonella in eggs back in the eighties. The US has had plenty of new diseases: West Nile Virus, monkeypox. It's especially common in places where there's a high wildlife diversity and lots of people doing lots of things in the environments: building new roads into forest, hunting and eating wildlife. We need to reassess our relationship with nature. First of all, we need to understand where these things come from and appreciate that when we build a road into the forest, it can be really beneficial to our economic success, but it also has a cost to it. And that cost is not just climate change or loss of acute species; it's also pandemics.

Unfortunately, while COVID may have convinced people and governments that international collaboration, surveillance and wildlife management are important, when it comes to why these outbreaks happen, and why scientists expect them to happen increasingly more often, the elephant in the room is us. Dennis Carroll...

Dennis - The biggest simple ingredient is population and population having high interaction with wildlife. The population explosion in China over the last century has meant urban settlements moving closer to wildlife domains, agricultural activities bringing human populations close to wildlife, and the disruptive effect of land use change, all creating a combustible situation where people and wildlife animals are interacting on a scale that is unprecedented.

Chris - If the driver is human population and that is going up at an increasing rate, what's the outcome? Are we going to see this even more often then?

Dennis - Well we are going to see it more often. As you said, population is increasing. We'll soon hit 10 billion, and by the end of the century, 11-12 billion people. So you can expect that, as we move into the 21st century, we're going to start seeing the consequences of that dramatic growth in human population. And the population dynamics of the world are changing dramatically. Asia, in fact, is contracting. China will have fewer people in 2050 than it did in 2000. But when we look at Sub-Saharan Africa, there you're going to see most of the growth; and in South Asia, in India specifically. So as we move into the 21st century, you can expect the risk profile of emerging diseases to follow suit with the population increase in these other geographic areas as well.

And according to Raina Plowright, as we keep shrinking the wild spaces of the world, we’re going to be gambling against the next pandemic more and more often...

Raina - At the moment, the way that we're crisscrossing the world with roads, fragmenting our ecosystems into smaller and smaller patches which then create larger edges, larger contact zones, we're certainly rolling the dice more often. We're rolling the dice thousands of times a day. But every time we have a new pathogen jump into the human population, we're taking the chance that it has just the right characteristics to be able to infect that person in the first place and then spread. And so many of these pathogens, they're probably even going unseen. For example, hospitals around the globe are full of people who have encephalitis or respiratory problems without any diagnosed aetiology. So no pathogen's actually ever isolated, there's no cause actually found. And this is probably happening all the time. These spillover events occur, someone gets sick, and we never hear anything about it.

Phil - It seems kind of inevitable though, right? I mean, what is there that we can do to stop more pandemics?

Raina - We need to look at what are the factors that really drive these events. And those factors are: having wildlife populations that are stressed, so perhaps more likely to be infected, more likely to be shedding the pathogens. And we see that with other pathogens like hendra virus in bats in Australia; when the bats are nutritionally stressed we she more viral shedding. We also will see it when there's more contact. So we need to limit human contact, especially with these novel populations; so limit the intrusions into forest, limit fragmentation, limit road development, and try to keep large, intact areas; intact areas of wilderness where animals can do their thing, they can seek their food, they can move freely, without having to come into human populations, without having to come into villages to look for food, and without having to come into contact with people because they're trying to make a living and survive.

Which means that even while we’re scrambling to survive this pandemic, we need to overcome any instinct to be short-sighted and we must start planning for the future. Peter Daszak...

Peter - I think that's partly human nature. We don't like to spend money and inconvenience ourselves for rare events, and pandemics are rare events. Even if they're once every 10 years, it's long enough between them to forget about the severity of the last one. We also have trouble justifying this to politicians who have to spend the money. You don't get voted in for saying, “we're going to spend millions of dollars to prevent a disease that we don't even know exists yet.” You get voted in for saying, “look how heroically I dealt with the ebola outbreak”, or the previous outbreak. So this is partly human nature. And I think we've got to realise we need to be smarter than that.

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