The anatomy of a pandemic
What have scientists uncovered six months on?
Tracking a killer
Investigating an outbreak is not unlike the work of any detective. It’s a race to the scene of the crime before any evidence disappears; witnesses are interviewed - and then the chase begins, to track down and contain the killer before they strike again.
But despite rallying an unrivalled international effort, coronavirus continues to advance, killing thousands of people everyday.
Six months on, what have scientists discovered whilst trying to contain coronavirus?
Raising the alarm
Understanding the origins of any virus is crucial, in order to predict how it will impact our health, and how fast it might spread. But, from the very beginning, coronavirus took everyone by surprise.
As much of the world prepared to welcome in the new year, Dr Li Wenliang was working in the emergency department of Wuhan Central Hospital where seven patients, all suffering from pneumonia - an infection of the lungs - had been quarantined.
Group messaging his colleagues in a private WeChat on 30 December, he shared his worst fears - was he witnessing a new wave of Sars (Severe Acute Respiratory Syndrome)?
Sars, another type of coronavirus, first emerged in China in 2003 and spread to 26 countries, infecting more than 8000 people.
However, what Dr Li had identified was not a second wave of Sars, but the first wave of the Covid-19 virus (Sars-Cov-2).
Three days after texting his peers, warning of a possible outbreak, Dr Li was detained by police, along with eight others, for “spreading rumours”, according to Chinese media.
Shortly after returning to work, Dr Li contracted Covid-19. He died on 7 February, aged 34, leaving behind his son and pregnant wife.
Scene of the crime
Situated in the newer part of town, Huanan Seafood Market was a hubbub of small stallholders, selling everything from live poultry, to fish, reptiles and wild game.
But throughout the last weeks of December 2019, as more and more doctors and nurses began to warn of a possible viral outbreak, it was health workers who first realised the connection - that the majority of their patients worked at Huanan Seafood Market.
On 31 December, Wuhan’s Health Commission filed their first official report to Beijing. The following day, the market was quarantined.
Today, scientists are unanimous in believing a large outbreak took place at the seafood market, but whether it was the place where the virus first emerged now looks unlikely.
Samples taken from both people and live animals at the market have since tested positive for Covid-19. Yet, according to medical researchers in Wuhan, the earliest human case of the coronavirus disease has subsequently been found to have occurred almost four weeks earlier than the outbreak at the market: an elderly man from Wuhan who developed symptoms as early as 1 December 2019 and had no conclusive links to Huanan Seafood Market.
Back in January, as health workers in Wuhan began to witness an explosion of cases across the city's hospitals, no one predicted the devastating speed with which the virus would spread, not only across China, but across the Asian continent.
Just nine days after the first reported death of a patient with Covid-19, on 11 January, new cases had already crossed from China to Japan, South Korea and Thailand.
And thus began the chase after a killer, in which, despite all the world’s advances in medicine and technology, we were always one step behind…
In just 6 months, Covid-19 has spread to 188 countries and infected over 7 million people
Profiling a killer
“Our first question is always, what is it?” says Professor of Immunology Kristian Andersen
Andersen's laboratory specialises in infectious disease genomics. They investigate how viruses jump from animals to humans and cause large-scale outbreaks.
Back in late December, within hours of those first cases being admitted to hospital, nasal swabs of the mystery virus were being analysed by scientists at the Wuhan Institute of Virology.
They were looking for its genome - its complete genetic code - which would reveal exactly what it was and how it might spread.
Genomes are essentially a long string of letters - the human genome, for example, is made up of over three billion genetic letters. A common flu virus is more like 15,000 letters, and encoded within this chain are all the instructions a virus might need to replicate itself millions of times over, resulting in the spread of disease and infection.
Deciphering the genome of a virus usually takes months, even years, to complete. However, with exceptional speed, on 10 January, scientists at the Wuhan Institute of Virology - led by Professor Yong-Zhen Zhang - published the first genomic sequence of Covid-19, the first, and arguably the most crucial, piece of the puzzle.
“As soon as we saw that first sequence, we knew immediately that it was a type of coronavirus - and that it was 80% identical to Sars,” says Professor Andersen.
Coronaviruses are a large family of viruses, hundreds of which are known to circulate among animals such as pigs, camels, bats and cats. Covid-19 is only the seventh coronavirus believed to have jumped from another animal to a human.
“Our second question is how can we diagnose it - which leads to testing and understanding the way the virus transmits,” says Prof Andersen.
“And the third question is how can we develop vaccines against it? All of which can be answered with the genetics as a blueprint for the virus.”
Professor Anderson says there is overwhelming evidence the virus originated in a bat.
“This ultimately started in a bat. We know this is a fully natural virus, because there are so many similar viruses found in bats,” he explains. “What we don’t know is how it got into the human population.”
Andersen’s team has studied another coronavirus found in a bat, which was 96% identical to Covid-19. They have also seen strong similarities with another corona-like virus found in pangolins, one of the most trafficked mammals in Asia.
Could the virus have jumped from a bat, to another intermediary animal such as a pangolin, where it picked up some extra proteins, before finally jumping to a human? For scientists, the investigation continues.
In China, just two days after sharing the first genetic sequence of Covid-19 with the world, Professor Zhang’s laboratory was closed by local authorities and their research licence revoked. According to Chinese media, no official reason was ever given - but the team’s contribution to the world had already taken root.
“Without that first sequence, we couldn't have started any of this work,” says Prof Andersen. “It’s all thanks to these scientists delivering crucial information at an unbelievable speed.”
Track, trace, isolate
As the pandemic took hold, efforts shifted from investigating the origins of the virus to containing the outbreak.
Contact tracers
South Korea, a nation of 51 million people, stands out as one of the most successful countries in the world in managing to contain Covid-19.
Much of this success has been attributed to the country’s ability to mobilise a small army of contact tracers: detectives trained to connect the dots between a positive Covid-19 case and all their most recent contacts. The tracers must then decide who should be instructed to self-isolate, or, in some cases, whether to quarantine an entire building or organisation, such as a hospital, care home or office.
With only a handful of cases throughout January and early February, many South Koreans thought perhaps a large outbreak had been avoided. However, in late February, from a single city, came a sudden escalation of thousands of cases reported within the space of only a few days.
The outbreak in Daegu city has since been attributed to the movements of one single person, South Korea’s superspreader - the now infamous patient 31.
Patient 31 tested positive for coronavirus on 17 February. It was only thanks to the work of contract tracers, that all her most recent contacts - which, shockingly, turned out to be more than 1,000 people in the space of 10 days - were tracked down and instructed to self-isolate, thus avoiding an even bigger outbreak.
As deputy of Daegu’s epidemiology team, Professor Kim Jong-Yeon is responsible for the city’s infantry of contact tracers - often former government employees, as well as junior doctors. He says only if people are evasive, do they use more rigorous methods - such as investigating their credit card transactions and their phone or GPS history. People such as patient 31.
“Patient 31, at first she didn't tell us she was from the Shincheonji Church. It was us, the contact tracers, who later discovered she was a member,” says Prof Kim.
With approximately 300,000 members nationwide, the doctrine of Shincheonji Church of Jesus claims their founder, Lee Man-hee, is the second coming of Jesus Christ and that only he can interpret the Bible. Many mainstream Christian churches in South Korea consider the group to be a cult and have long criticised their aggressive recruitment of young people.
But patient 31 has not become infamous simply for covering up her affiliation with Shincheonji Church. As contact tracers uncovered, in the 10 days prior to being tested - despite showing symptoms - she travelled around the city of Daegu coming into contact with more than 1,000 people.
After being involved in a car accident on 6 February, patient 31 was admitted to hospital on 7 February, where she came into close contact with an estimated 128 people. She then temporarily discharged herself in order to return home to collect personal belongings, a two-and-a-half-hour round-trip, before returning to hospital. Later that week she discharged herself multiple times, once going for lunch with a friend, and twice in order to attend a a two-hour church service with a 1000-strong congregation.
Due to the secretive nature of the Shincheonji Church, Prof Kim says the hardest part of the investigation was trying to establish who also visited the church during that week.
“We finally secured a list of all 9,000 members of the church. At first, we started to call and ask all of them if they had any symptoms. About 1200 people told us they did, but some people refused to get tested and self-quarantine.”
With hundreds of individuals reluctant to reveal their association with the secretive church, the professor says they were left with no choice.
“It became a matter of how quickly we could separate those church members from the rest of Daegu’s citizens. So the government issued an executive order for all church members to self-isolate.”
The city’s rigorous investigation of all new cases, combined with comprehensive testing, quickly curbed the spread of the virus - and by early April, the city of Daegu reported zero new cases of Covid-19.
However, elsewhere in the world, the virus continued to advance unabated. For the scientific community, it became vital to track the virus, not only over borders, but across continents.
The answer to this problem lay in the genome, clues left behind in the genetic code of the virus as it began to replicate and spread.
A trail of evidence
A single purple dot over Wuhan, representing the first few nasal swabs taken from Covid-19 patients and analysed by scientists to reveal the genome of the virus - a chain of 30,000 genetic letters containing all the virus needs to replicate and spread.
Map: Nextstrain
Since the discovery of the genome by Professor Yong-Zhen Zhang’s team back in January, scientists around the world have continued to analyse tens of thousands of nasal swabs, uploading their results to GISAID, one of only a few open source databases.
By repeatedly sequencing the genome thousands of times, as it spreads, scientists are able to track mutations in the genetic code - tiny mistakes, ‘typos’ in the chain of letters. Like a trail of clues left behind by the virus, sequentially following a string of mutations can show how the virus is spreading over borders.
For example, if a sample taken from a patient in New York reveals three single mutations, and several samples from Wuhan also carry those same three typos in their genome, it's highly likely all these cases came from a single transmission. By subsequently establishing a timeline of events, experts are able to understand when, and how, the virus jumped from Wuhan to New York.
Map: Nextstrain
With more than 37,000 samples now sequenced from all over the world, the devastatingly infectious nature of Covid-19 has been fully revealed.
Map: Nextstrain
Epidemiologist Dr Emma Hodcroft works with Nextstrain, a group of scientists and coders who extract key information from the tens of thousands of sequences uploaded to GISAID, in order to create an open source map - a real-time snapshot of the mutating genome as the virus spreads around the world.
“By tracking the genome, we are able to get insights beyond simply talking to people. They may not know when they were infected or where they have been. But genome data is much more reliable,” says Dr Hodcroft.
Especially, where there is a lack of information, such as Iran.
A trail of evidence
A single purple dot over Wuhan, representing the first few nasal swabs taken from Covid-19 patients and analysed by scientists to reveal the genome of the virus - a chain of 30,000 genetic letters containing all the virus needs to replicate and spread.
Since the discovery of the genome by Professor Yong-Zhen Zhang’s team back in January, scientists around the world have continued to analyse tens of thousands of nasal swabs, uploading their results to GISAID, one of only a few open source databases.
By repeatedly sequencing the genome thousands of times, as it spreads, scientists are able to track mutations in the genetic code - tiny mistakes, ‘typos’ in the chain of letters. Like a trail of clues left behind by the virus, sequentially following a string of mutations can show how the virus is spreading over borders.
For example, if a sample taken from a patient in New York reveals three single mutations, and several samples from Wuhan also carry those same three typos in their genome, it's highly likely all these cases came from a single transmission. By subsequently establishing a timeline of events, experts are able to understand when, and how, the virus jumped from Wuhan to New York.
With more than 37,000 samples now sequenced from all over the world, the devastatingly infectious nature of Covid-19 has been fully revealed.
Epidemiologist Dr Emma Hodcroft works with Nextstrain, a group of scientists and coders who extract key information from the tens of thousands of sequences uploaded to GISAID, in order to create an open source map - a real-time snapshot of the mutating genome as the virus spreads around the world.
“By tracking the genome, we are able to get insights beyond simply talking to people. They may not know when they were infected or where they have been. But genome data is much more reliable,” says Dr Hodcroft.
Especially, where there is a lack of information, such as Iran.
Mystery links
In late January, Dr Hodcroft and the Nextstain team began to notice a number of samples, all with extremely similar genomes, sharing often identical mutations, but from eight different countries, including Australia, New Zealand, Germany, UK, US, China and the Netherlands.
Following the trail of evidence back in time, at first the team couldn't pinpoint where this rogue group of samples had come from.
“They were clustering together really closely on the tree," says Hodcroft. "This was a surprise, because the people seemed to have nothing else in common. But then we discovered several of the Australian samples had a history of going to Iran.”
“This was really powerful, because at the time we had no samples from Iran. But this discovery meant we could say, with high confidence, all these samples were either infected in Iran or by someone who had recently been to Iran.”
Tracking the genome is such a powerful tool because the virus mutates relatively infrequently. Therefore, even a few samples is enough for scientists to understand how the virus is spreading across an entire region.
Looking at these samples from Iran, like siblings and cousins on a family tree, the Nextstrain team were able to conclude, not only did these samples all come from a single original transmission in Iran, but that the entire outbreak in Iran was also highly likely to have originated from that same single transmission.
Contact tracers on the ground have since attributed the main outbreak in Iran as originating in the holy city of Qom. With thousands of religious tourists visiting everyday, the virus spread from Qom to every province in Iran in less than two weeks.
Through contact tracing and remote tracking of the genome, scientists have revealed the true speed and stealth with which Covid-19 has spread around the world. However, despite all of the discoveries of the past six months, experts remain one step behind - unable to predict when and where the virus will next strike.
When it comes to containing Covid-19, one huge problem remains: the virus' chaotic and unique ability to move through a population sometimes unleashing a fatal disease, but more often, causing mild to no symptoms at all.
Investigating the silent spread of Covid-19 among individuals with no symptoms is inherently difficult. However, from one tiny rural village in northern Italy came an important piece of the puzzle.
An invisible threat
Italy’s first death from Covid-19 took place, not in one of its many bustling cities, but in the small, isolated village of Vo’, in the region of Veneto. Home to around 3,000 people, Vo’ lies at the base of the Euganean hills, a national park less than an hour from Venice.
As soon as the country’s first fatality was announced on 21 February, local authorities took the decision to seal off the entire village and began repeatedly swab-testing all residents, regardless of whether they showed symptoms of not. Scientifically, this created a unique opportunity, with several thousand people being repeatedly tested whilst living in lockdown.
Leading the investigation was local microbiologist, Associate Professor Enrico Lavezzo. He explains the most important finding of their study was what he calls the “silent spread” of the virus: the unexpectedly huge proportion of people who tested positive, but who had mild or no symptoms.
“More than 40% of people who were carrying the virus were not even conscious that they could be infecting other people. This is a huge problem with regards to containing such an infectious disease," says Prof Lavezzo.
“Most symptomatic people will stay home, but most asymptomatic people will behave normally. They’ll go out, meet people, come into close contact with others - without even knowing they can pass on the virus.”
Lavezzo's group was one of the first to establish the vast scale of the problem of asymptomatic cases. Other studies have since established estimates as high as 70%.
The other surprising discovery of the Italian investigation was that, out of 3000 villagers, not a single child under 10 tested positive.
"We're not saying children cannot be infected. This has been shown by other studies. But the fact that at least a dozen of them were living with infected people, but were themselves not infected is strange and needs further investigation," says Prof Lavezzo.
The main reason Covid-19 continues to advance unabated, is because compared with other coronaviruses, it appears able to hijack huge numbers of people, who unwittingly aid the virus in spreading it even further.
But why is Covid-19 so unique in its ability to cause such a huge range of symptoms, from a mild cough to potentially fatal breathing difficulties? And based on Prof Lavezzo's results, why would children be less affected?
A deadly combination
Scientists have discovered the virus can only enter the human body one way, by latching on to specific receptors found on the surface of human cells, known as ACE-2.
Professor Michael Farzan’s laboratory was the first to discover the ACE-2 receptor, during the Sars outbreak in 2003.
However, as Michael explains, the problem with ACE-2, is that they exist all over your body, inside your nose, lungs, intestines, even your heart, kidneys and brain.
This vast spread of ACE-2 is why Covid-19 causes such a broad range of symptoms. From an infection in your nose, leading to a loss of sense of smell, to an inflammation in your lungs, causing a severe cough.
Commonly, most viruses are either good at spreading or can cause severe disease. Covid-19 is more dangerous because it’s good at both.
By infecting the upper airways, the nose and upper lungs, inflammation causes coughs and sneezes, which rapidly spread the disease. Meanwhile, infecting the lower airways can cause serious, potentially fatal, breathing problems.
Evidence as to whether children are any more or less likely to pass the virus on than adults remains unclear.
The UK government's Scientific Advisory Group for Emergencies (Sage) said the "balance of evidence" suggests children might be both less likely to catch it and, if they do catch it, less likely to pass it on. However, they also said "the evidence remains inconclusive".
Professor Farzan says scientists now have evidence that children, who account for less than 2% of cases, have fewer ACE-2 receptors in their lower lungs compared to adults.
“This means that children will be less prone to the illness, at least the kind of severe pneumonia adults have experienced,” says Prof Farzan.
However, they still have a high number of the receptors in their upper lungs, he explains.
“They will still be capable of transmitting the virus to other individuals, because that upper respiratory tract is really important for the virus moving on to the next person."
It's down to the devastating efficiency with which the virus multiplies and moves on that, despite six months of investigation and scientific discovery, scientists believe the only way to truly bring an end to the pandemic - and avoid future waves of the virus - is a preventative vaccine.
The race for a vaccine
There are currently 124 different groups vying to be the first to develop a vaccine against Covid-19.
Professor Jorge Kalil, medical director at the University of Sao Paulo, leads one of the few trials taking place in Brazil - a country paralysed by coronavirus, but whose president, Jair Bolsonaro, continues to attend anti-lockdown rallies, despite regional authorities ordering local lockdowns in most major cities across the country.
In response to some groups claiming a vaccine could be ready as early as September, with manufacture and distribution then taking a further 12 to 18 months, Kalil remains sceptical. He says it’s about remaining rigorous - not rushing to come first.
“We have to go as fast as we can. But I don't think the first to arrive will be the winner. It’s not a car race. The winner will be the best vaccine, the one that works for the most amount of people - ideally 90% - and stops both symptoms and transmission.
Kalil believes to truly end the pandemic, what the world needs is a vaccine that works for older people and those with underlying health conditions. He says it is these individuals who will struggle the most to develop antibodies, our body's natural defence mechanism in response to a vaccine or an infection. So unless a vaccine works for the majority of people, including the most vulnerable, he believes Covid-19 will continue to spread.
He also believes it’s imperative all countries are able to access a vaccine, in order to prevent future waves.
“The problem is money and politics. Here in Sao Paulo [Brazil], you have the rich guys isolating in their beautiful houses, but then a humble family could be eight, nine or 10 people sharing a single room. How are they supposed to isolate?
“In order to really end it for everyone, we need a very good vaccine. There is no other way out.”
Credits
Reporter - Claire Press
Additional reporting by - Bugyeong Jung
Illustrations - Charlie Newland
Graphics - Zoe Bartholomew, Daniel Dunford, Prina Shah, Dominic Bailey, Alison Trowsdale
Images - Getty, BBC
Editors - Ben Allen and Jacky Martens
Thanks to Victoria Lindrea, Courtney Tims, Angelo Attanasio, Juliana Gragnani and Woongbee Lee
Published 6 June 2020