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By Roger Highfield on

Coronavirus: Hunting down COVID-19

Roger Highfield, Science Director, talks to Kari Stefansson, whose genetic sequencing project has revealed how the UK infected Iceland, that children don’t seem to infect parents, and how to control COVID-19.

Kari Stefansson is the CEO of the Icelandic company deCODE genetics in Reykjavík, which has studied the spread of COVID-19 in Iceland with Iceland’s Directorate of Health and the National University Hospital.

His edited answers are in italic to distinguish them from my commentary.

what does your testing programme tell us?

Because Iceland’s epidemic is so well documented, we are able to provide the world with a large amount of information on how the infection was caught, the way it spreads, and how it mutates as it spreads. This ‘molecular epidemiology’ can reveal the geographic origin of the virus in every single case.

First and foremost, other nations should look at how Iceland contained the pandemic because it is working. 

However, because the virus has spread to the extent that it has, unless we continue to test and isolate, track contacts, and quarantine, we are likely to fail in our efforts to contain the virus.

what percentage of iceland’s population have you tested?

We have already tested 12 per cent of the Icelandic population of 360,000 people. We not only test for the presence of the virus, we also sequence the virus.

Sequencing the virus enables scientists to determine its precise genetic code, which is ‘written’ in a sequence of four different chemical ‘letters’, carried in the form of RNA, ribonucleic acid.

Like DNA, RNA is a long, chain-like molecule, a nucleic acid, that encodes information in this sequence of letters.

It is trivial because the genetic code of the virus is only 30 kilobases.

These are the 30,000 ‘letters’ of viral code that carry the instructions to make the virus’s 29 proteins, such as the spike protein, S, used by the coronavirus to invade human cells; NSP3, NSP 4 and NSP6, which create virus-making bubbles inside infected cells; and NSP7 and NSP 8, which copy viral genetic code for new viruses.

In mid-April we started to do antibody screening as well (this reveals if someone has already been infected). 

In attempting to carefully map the molecular epidemiology of COVID-19, we hope to provide the world with data to use in the collective global effort to curb the spread of the disease.

Applied Biosystems 370A Prototype Automated DNA Gene Sequencer, by Applied Biosystems Inc., Foster City, San Mateo county, California, United States, 1987.
Prototype Automated DNA Gene Sequencer, 1987. Part of the Science Museum Group Collection.

how have you managed to test a greater percentage of your population than anywhere else?

Iceland started to screen people at high risk and with signs and symptoms of COVID-19 for the virus at the beginning of February and had its first case on 28 February.

On 13 March, deCODE started to screen the population in general, through volunteers who had signed up.

We reported that roughly 0.8 per cent was infected earlier this month but now think the distribution is about 0.6 per cent and is decreasing, so the Government’s containment efforts have been working.

what is the containment philosophy in iceland?

We have taken a middle of the road approach, rather than lockdown. Elementary schools, childcare and stores are still open, for example, but we have banned gatherings of more than 20 people and closed theatres and concert halls.

We have done it in a relaxed way but with three exceptions: we have screened more than anyone else to find the cases looming in society that have not been caught by the healthcare system; we have aggressively tracked people they have come into contact with; and we have equally aggressively put them in quarantine.

This has worked.

how does this compare with other countries?

I think it is inexcusable that the UK was not more vigilant, notably in using PCR testing.

This is the basic test for the presence of the SARS-CoV-2 genetic code, though this in itself does not provide the genetic sequence of the virus.

With America, it has amazing resources and actually taught us how to do the screens we are doing now. They invented the technology but unfortunately were slow to apply it to their own people.

I think this epidemic would have looked totally different if countries like the US, UK and other European countries had been more vigilant.

Britain has been at the forefront of the molecular genetics revolution, from deducing the double helix structure of the genetic material DNA to developing DNA fingerprinting and genetic sequencing (by double Nobel prize-winner Fred Sanger, and creating the world’s best-selling drugs.

how did the infection arrive in iceland?

Screening those at high risk and who showed symptoms revealed the first cases came from Austria and Italy – people who were on skiing vacations in the Alps.

The authorities in Iceland issued a warning to Austria that a large number of cases were coming from Austria to Iceland and they would have to do something about it. They ignored the warning.

Those first cases were put in isolation and everyone they came into contact with were quarantined to contain the spread.

what did your wider population screen reveal?

We found that a large number of the original cases came from the UK.

The spread of the virus was much greater in the UK early on than people realised. They might have even preceded those from the Alps.  We don’t know exactly, but these cases could be from as early as February. (See Table 2 in our paper) .

In the early targeted testing of those coming from high-risk areas in the Alps (Jan 31-March 15) there are almost no UK origin samples but that was because it hadn’t yet been listed as a high-risk area.

But as soon as the population screening started, it was dominated by UK-origin virus, so this was spreading quickly through the Icelandic population from February.

The Austrian/Italian cases were from what is called the A2 clade (a clade is a group of viruses united by their descent from a common viral ancestor), while the UK cases were from the A1 clade. The original outbreak in Wuhan, China, is known as the A clade.  We have also screened for mutations seen in the west coast of the US, the B1a clade.

how much does the covid virus, sars-cov-2, mutate?

Even though the mutation rate is low (that is the rate at which the ‘letters’ in the genetic sequence of the virus change because of errors in the way the virus is copied in human cells) it infected so many people that we found a high diversity of sequences, an enormous number of mutations.

We published the first data in the New England Journal of Medicine and you can see 528 mutations scattered though the genome, even in the receptor binding domain of the spike protein (this spike, which has been studied in huge detail, is one of the corona of protrusions around the virus that enables it to invade human cells).

We found 291 mutations in Iceland that have not been seen elsewhere. However, there is no evidence of a different biology of the virus in A1 and A2 and so on.

can we see the virus evolve?

Yes. This kind of virus – an RNA virus – is known to evolve and mutate more quickly as they reproduce in a human host than, say, DNA-based viruses, such as adenoviruses (one of the causes of the common cold) and herpesvirus.

These mutations occur randomly.

Some are never picked up, because they disable the virus. Many have no effect. Others may but we don’t know if they make the virus more or less lethal – as Kari Stefansson told me: That is a big question.

Trees have been a central metaphor in evolutionary biology ever since Charles Darwin, whose idea of natural selection gave biology its central guiding principle, sketched his first evolutionary tree in 1837.

Charles Darwin portrait image
A Carte de Visite photograph of Charles Darwin from the Science Museum Group Collection.

Molecular epidemiologists use the genetic sequences to create a family tree of the virus and can figure out the rate of mutation (between two and two and a half changes in genetic letters per month, according to Kari Stefansson).

They can deduce, for example, how the very first infection occurred in late November in Wuhan, China.

The virus was natural, and not created in a lab, according to Andrew Rambaut of the University of Edinburgh and colleagues, and is closely-related to bat and pangolin (a scaly anteater) coronaviruses, perhaps even a blend of bat and viruses that emerged by a genetic mixing process, called recombination, in a bat, pangolin or another species.

To visualize the evolution of the virus, scientists construct a ‘phylogenetic tree’, where the trunk of the tree is designated A, the virus which originated in Wuhan (note, however, that the bat virus, although the closest non-human virus to SARS-CoV-2, is still extremely divergent and a study tracking the infection from Wuhan has been criticised for not taking this diversity into account).

To help understand how the virus evolved the branches are categorised in arbitrary lineages or clades, each given a label such as A1, A2 and so on, where groups of viruses are similar and united by a common ancestor a few mutations beforehand.

Genomic epidemiologists can work out who has infected whom as follows: if a virus sampled in the UK has three specific mutations and another infection sampled in Iceland has the same three mutations plus a novel mutation, scientists can infer the coronavirus was transmitted from the UK to Iceland.

They can also estimate how long the virus has been circulating in a country by using the rate at which the virus is mutating, the number of mutations seen in local strains, and the genetic sequences from the country of origin.

You can see the global phylogenetic tree here, created by Nextstrain, an open source platform to track disease agents, and the tree for Europe, which shows UK cases as early as January. When it comes to Iceland, see Figures 3B and 3C in Kari Stefansson’s paper.

Here’s how to interpret phylogenetic trees.

are some people are more at risk than others?

The clinical diversity of COVID-19 is another big question. Some people describe it as a mild cold. Others end up on a respirator and die.

Men are much more likely to become infected than women. If women get infected, they do not get as sick as men.

Children under 10 are less likely to get infected than adults and if they get infected, they are less likely to get seriously ill. What is interesting is that even if children do get infected, they are less likely to transmit the disease to others than adults. We have not found a single instance of a child infecting parents.

There is an amazing diversity in the way in which we react to the virus.

how can we account for the range of severity of covid-19?

One possibility is that these mutations generate different strains of the virus that cause disease of different severity. Another possibility lies in the genetics of the patients, with some people being born susceptible to the virus and others resistant.

Or perhaps some of us were exposed to a sufficiently similar coronavirus to give them partial immunity to COVID-19, what we call cross reactive immunity.

This is what people all over the world are ferociously working on since it is the key to dealing with the pandemic intelligently.

You also have the genetic sequence of infected people – what does that reveal?

The first thing you check is the proteins used by the virus to invade human cells, called ACE2 and TMPRSS2. 

The SARS-CoV-2 virus requires two key proteins, called ACE2 and TMPRSS2, to enter human cells: the first is a ‘receptor protein’ that the virus attaches to, while the second is a so-called protease, an enzyme that activates viral entry into the cell.

We found nothing in the ACE2 receptor – there is no sequence diversity in the receptor that sheds light on susceptibility. Nor TMPRSS2 either. No other clues have emerged yet.

how long does immunity last?

We have screened 3000 people or so in the last week so we cannot yet shed any light on how long lasting the immune response is.

We are working on the data but it is not going to be a simple story. I have been working on all kinds of common diseases over the past quarter of a century.

Imagine, at the age of 71, having a disease falling into your lap where nothing is known about it, and no question has been answered. I am having a feast in the middle of the famine and I feel a little bit bad about it.

The World Health Organisation said on April 25 there is currently no evidence that people who have recovered from COVID-19 and have antibodies are protected from a second infection.

is the uk doing molecular epidemiology too?

Yes, a huge effort is under way. The £20 million COVD-19 Genomics UK (COG-UK) consortium is a network of labs created to deliver large-scale and rapid whole-genome virus sequencing to local NHS centres and the UK government.

The consortium has already read the genetic sequence of more than 10,000 viruses in the UK and is aiming for a quarter of a million. You can see their current analysis of worldwide COVID-19 lineages circulating in the UK.

‘We are now the world’s largest producer of coronavirus genomes,’ says Nick Loman, Professor of Microbial Genomics and Bioinformatics, University of Birmingham.

Researchers around the world are sharing their data on GSAID, the Global Initiative for Sharing All Influenza Data, an initiative started by the World Health Organisation in response to the threat of bird flu.

Although the percentage of Iceland’s population that has been tested is much greater, ‘Iceland has a very small population compared with us,’ said Loman.

The consortium gets the genetic sequence of the virus from samples identified as positive by testing efforts such as those in universities, public health laboratories across the UK and also NHS hospitals, along with the Lighthouse Labs in Milton Keynes, Alderley Park and Glasgow, which test thousands of patient samples each day for coronavirus, in what is the biggest network of diagnostic testing facilities in British history.

‘The biggest hurdle for both testing and sequencing genomes isn’t the laboratory aspect as much as the logistics, from getting the samples to linking the results back to an individual’, said Loman.

They can in some cases also link the virus genetic sequence that caused an infection with the patient’s genetic sequence because the UK has major programmes to read the entire genetic sequence of its population.

Notably through the efforts of UK Biobank to follow the health of half a million people, the 100,000 people studied by Genomics England, and a consortium called ISARIC, an open global community of scientists and doctors set up in 2016 to see how a patient’s genetic make-up influences how they fare when infected.

This will help understand if some people are more resistant or susceptible. Genomics can also reveal how, for example, a care home or ward was infected.

Government Chief Scientific Adviser, Sir Patrick Vallance said: ‘genomic sequencing will help us understand COVID-19 and its spread. It can also help guide treatments in the future and see the impact of interventions.’

Fiona Watt, Executive Chair of the Medical Research Council, part of UK Research and Innovation, added: ‘The UK is a leader in cutting edge genome sequencing science.  The ambitious and coordinated response of our research community to the COVID-19 challenge is remarkable.’

who was ‘patient zero’ in the uk?

‘We hate that term,’ said Loman. ‘If someone is unlucky enough to become infected, not show symptoms and spread COVID-19 around, they should not be blamed, like Typhoid Mary.‘

Moreover, the genomes so far show that there were many separate introductions of COVID-19 into the UK in late January and February, predominantly from other European countries visited by Britons around the time of February half term.

The UK has hundreds of separate COVID-19 lineages, ‘each of these represents an individual chain of transmission that needs to be halted’.

However, there is an issue of sample bias, said Loman: to really understand how COVID spread from nation to nation we need to ensure truly random international sampling, since the results might be warped if we only test in the places where we are able to test.

Loman explained: ‘Not all countries are currently producing or sharing very much genome data, so transmissions to and from that country are simply invisible using this approach’.

what is the best testing strategy?

Lots of work is under way to determine the best strategy, for instance using information from computer models and new insights into how the virus spreads.

Weekly screening of healthcare workers and other at-risk groups irrespective of symptoms, would reduce their contribution to transmission by up to one third, on top of reductions achieved by self-isolation following symptoms, according to a study of how testing can control the pandemic by Nicholas Grassly, Marga Pons-Salort and colleagues at Imperial College London.

Another study revealed that more than half the residents of an American nursing facility who had positive tests were asymptomatic, underlining how symptom-free carriers play a major role in the transmission of SARS-CoV-2 and prompting calls for testing of asymptomatic people in care homes.

A study of two hospitals along with public areas in Wuhan, China, reveals hotspots of airborne virus RNA, notably in areas prone to crowding, whether aerosols carrying the virus have the potential to infect others was not studied by the researchers, who report their work today.

can you track how the virus enters the body?

Yes. Scientists have used a cell atlas to show how the virus could be transmitted to the body.

These vast atlases show which of the hundreds of different cell types in the human body are using which subsets of our 20,000 genes, notably the ACE2 and TMPRSS2 genes that encode the human proteins exploited by the COVID-19 virus to infect human cells.

Scientists, including Sarah Teichmann at the Wellcome Sanger Institute near Cambridge, discovered that cells in the nose (known as goblet and ciliated cells) have high levels of these entry proteins.

These two key entry proteins were also found in cells in the cornea. This suggests another possible route of infection via the eye and tear ducts.

And they were present in the lining of the intestine, so it could be that faeces carry the virus too.

The high transmission rate of COVID-19 could be explained by the study, which was conducted by the Sanger with the University Medical Centre Groningen, University Cote d’Azur and CNRS, Nice.

what is the state of the pandemic?

You can get the latest news on how far the pandemic has spread worldwide from the Johns Hopkins Coronavirus Resource Center or from the Robert Koch-Institute, Berlin, view the UK hotspots identified by an app, check the number of UK COVID-19 lab-confirmed cases and hospital deaths, and the overall number of deaths from the Office of National Statistics.

There is more information in my earlier blog posts, from the UKRI, on this COVID-19 portal and Our World in Data.

The Science Museum Group is collecting objects and ephemera to record the public health emergency for future generations.