SA team cracks the code that tells us the origins of country’s Covid-19 outbreak

A worker in a protective suit examines specimens inside a laboratory following an outbreak of the novel coronavirus in Wuhan, Hubei province, China. Picture taken February 6, 2020. China Daily via Reuters
A worker in a protective suit examines specimens inside a laboratory following an outbreak of the novel coronavirus in Wuhan, Hubei province, China. Picture taken February 6, 2020. China Daily via Reuters

A team of local scientists has successfully put together the first genetic fingerprint – or genome sequence – of severe acute respiratory syndrome (Sars)-Covid-2 (the virus that causes Covid-19) found in South Africa. Spotlight spoke to two of the scientists to learn more.

Together with the National Institute of Communicable Diseases (NICD), the University of the Western Cape’s SA National Bioinformatics Institute (Sanbi) cracked the code that could unlock the origins of the country’s outbreak, and help healthcare workers and government better track and trace the spread of the virus.

Spotlight spoke to Peter van Heusden, Sanbi researcher and co-author of the new report on the sequence, and Dr Mushal Allam, a medical scientist with the NICD’s Centre for Respiratory Diseases and Meningitis, who worked on the sequencing, about what this accomplishment means for the future of South Africa’s fight against the Sars-Covid-2 virus.

Van Heusden said: “This is a problem [affecting the whole of society] that we have to face with every set of skills that we’ve got. It did feel fulfilling that the training I’ve put myself through for several years can be used for something more than making a research paper.

“I’ve been very actively networking with my colleagues around the continent and around the world to make sure information flows as quickly as possible. In fact, as soon as this hit the radar screens in January, I was already talking to [Allam], asking when we would be able to sequence this thing,” he said.

The science background

If you took biology in high school, you might remember learning about DNA and RNA.

DNA is our genetic material, or basically the book containing all of our traits (like eye and hair colour), while RNA is the messenger between our DNA and the protein factories in our cells called ribosomes.

DNA is stored in the cell’s nucleus, which can in a way be seen as the “brain” of the cell.

The RNA, or messenger RNA (mRNA), takes information from our DNA in the nucleus straight to the ribosomes, which are in the cytoplasm (a yellow-looking solution) in our cells.

Think of the RNA as someone delivering specific instructions to the ribosome’s factory workers on how to make proteins that our bodies need. Normally, our cells are constantly producing new, good proteins, which is the ribosome’s job. However, when we become infected with a virus like Sars-Covid-2, something different happens in our cells.

Sars-Covid-2 is a single-strand RNA, and when it reaches our cells, it sneaks into the cytoplasm and behaves just like mRNA. However, it delivers bad instructions to our ribosome protein factories, resulting in the production of proteins that make us sick. Put differently, Sars-Covid-2 may act like messenger RNA, but it delivers the wrong message to our bodies. This is what makes the virus so dangerous.

How to sequence a genome

For this genome, the NICD used a sample from one of South Africa’s first confirmed cases infected with the Sars-Covid-2 virus, a patient from KwaZulu-Natal who had returned from Italy.

In the sample, scientists had human DNA and RNA, as well as the Sars-Covid-2 RNA.

This bug is not easy to sequence.
Dr Mushal Allam

To sequence the virus, they first had to separate it from everything else.

“Currently, we’re using a big, difficult method to sequence the virus,” said Allam.

Utilising what is called sequencing kits, Allam and his colleagues have to separate the human DNA from the virus and deplete the human RNA, leaving just Sars-Covid-2 to work with.

Afterwards, the virus RNA is checked for quality, and then the sequencing process begins.

With the NICD’s current technology using an Illumina sequencer (Illumina is a brand name), the sequence is delivered in small parts of about 150 base letters at a time.

After the sequencing is finished, scientists have to assemble the sequence to construct the 29 000 base-letter RNA strand of the virus.

“This bug is not easy to sequence,” Allam told Spotlight, adding that most of the readings were contaminated by human DNA and RNA.

Allam said that, since the outbreak, the NICD had prioritised the use of two sequencing machines just for Sars-Covid-2. With this technology, it can take five to six days to sequence one sample at R7 000 per sample.

The future of Sars-Covid-2 genome sequencing in SA

According to Allam, South Africa was well-equipped to sequence during the pandemic in terms of facilities, but cost, timelines and the procurement of Sars-Covid-2 sequencing kits were big challenges.

However, work was under way to cut the cost of sequencing for one sample down to between R400 and R500 and new, more time-efficient sequencing machines were in South Africa’s very near future, he said.

“The World Health Organisation and the Africa CDC labs have asked [the NICD] to sequence some genomes from African countries that don’t have these technologies,” said Allam.

Other countries, including the Democratic Republic of Congo, Nigeria and Senegal, have also sequenced Sars-Covid-2 genomes.

According to the website of the Global Initiative on Sharing All Influenza Data (Gisaid), more than 5 000 Sars-Covid-2 genomes have been sequenced to date, with about 62 being from Africa, said Allam.

Researchers place test material inside the laborat
Researchers place test material inside the laboratory refrigerators for Covid-19 swabs production at UniTo Biotech Department in Turin, Italy. Picture: Stefano Guidi/Getty Images

Using genomics to map a pandemic

The sequencing data compiled by the NICD was shared with a project called Nextstrain, which then created what is called a phylogenetic tree, or a family tree of viruses.

This tree can help scientists better understand where each of these genomes come from and how they are related.

For example, South Africa’s Sars-Covid-2 genome sequence has six unique differences compared to the original genome from Wuhan. Scientists can now see, using phylogenetics, that it’s likely that South Africa’s Sars-Covid-2 came from Europe or North America, which has very similar sequences.

By constructing this so-called family tree, not only can scientists track the origins of an outbreak, but they can develop a better sense of what the pandemic looks like overall.

We can understand the life cycle, though it’s not strictly alive, and we can understand the way that its proteins work and interact with our proteins, and that is important for [treatment] therapies.

Mutations don’t mean different strains

When talking about differences in the sequence, otherwise called mutations, it’s important to note that this does not mean there are different strains of the virus.

Van Heusden said: “Differences seen in the collection on Gisaid are minor, less than 100 bases across the whole 29 kilobase genome. There have been some more dramatic differences noted, such as deletions in parts of the genome, but these mostly seem to be related to culturing the virus in cells.”

Remember that Sars-Covid-2 is a single-RNA strand made up of 29 000 base letters. Three of these letters at a time make up a single amino acid, and a group (or chain) of amino acids make a protein. However, different combinations of these three letters don’t mean a different amino acid will be produced.

For example, if you have two parts of red paint and one part yellow, by mixing them you will still get the colour orange, no matter the order in which you mix them.

For South Africa’s Sars-Covid-2 genome, there were only two instances where different amino acids (or paint colours) were produced (this is called non-synonymous), but they showed no significant difference to protein structure – in other words, how the virus affects our bodies.

Taking all of this into consideration, with the available data, Van Heusden said scientists were confident that currently no other strain of Sars-Covid-2 existed globally.

Can sequencing be used to help create a vaccine?

“The genomics let us understand the virus’ proteins,” explained Van Heusden. “We can understand the life cycle, though it’s not strictly alive, and we can understand the way that its proteins work and interact with our proteins, and that is important for [treatment] therapies.

“We can also understand, from the diversity of genomics, which parts of the virus are stable and which parts are not. When you’re making a vaccine, that is very important information.”

Van Heusden said that Moderna, the first company to do a human clinical trial to protect against Sars-Covid-2, was using a new approach to making a vaccine.

“Normally what you do is use a weakened or killed version of the virus, or just bits of the actual virus. What Moderna is doing is making its vaccine [so that it] would inject RNA into a cell which will be made into [a new kind of] protein, which will then [cause] an immune response. It won’t be like an active virus, it’s just part of the virus that will be used to make the vaccine.”

This kind of vaccine where a small part of the virus’ RNA is used to make the vaccine is called an mRNA vaccine.

Van Heusden noted that, while sequencing was invaluable information for vaccine research and production, the primary use was to assist in tracing the virus and mapping the pandemic as a whole.

Therefore, the sequencing of South Africa’s Sars-Covid-2 virus could help government to improve contact tracing and testing.

. This article was produced by Spotlight – health journalism in the public interest


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