A new case of Covid-19 pops up in a New Zealand town.
Did it come from another group of infected – as happened when a case linked to Auckland's Marist College cluster emerged in Christchurch – or was it passed along from someone else at the local supermarket?
New Zealand scientists are working on a clever way of untangling the plate of spaghetti that is the community spread of Covid-19, through decoding each new case's genetic jigsaw.
"We've just finished analysis of two suspected community spread cases for which, in both cases, genomics provided leads to where infection might have happened," said Dr Joep De Ligt, a scientist at ESR.
"This will help inform further contact tracing and containment measures."
In just 20 years, genome sequencing has gone from a lengthy exercise costing billions, to one where scientists can decode pathogens in near real-time, for the cost of just a few hundred dollars.
Unsurprisingly, the particular pathogen behind the Covid-19 pandemic has come under intense focus.
On positive virus samples sent to his lab, De Ligt has been carrying out what's called whole genome sequencing – or determining the complete genetic sequence of SARS-CoV-2 at the same time.
First sequenced by Chinese researchers, the SARS-CoV-2 genome is a molecule comprised of ribonucleic acid, or RNA.
It packs about 30,000 bases, or letters, containing 15 specific genes – among them the "S" gene which codes for a protein on the surface of its viral envelope.
Being an RNA molecule, the genome is single-stranded; the human genome, by comparison, is a double helix of DNA, or deoxyribonucleic acid, containing about three billion bases and around 30,000 genes.
These SARS-CoV-2 genome sequences - often completed in less than 24 hours - have allowed scientists crucial insights into the origin and spread of the virus, and pointed vaccinologists to specific parts of its protein structure to target.
Amid cautious optimism that New Zealand may have acted in time to be able to stamp out the virus, it's also expected genome sequencing will play a big part in mopping it up here – especially when it comes to assessing suspected cases of community transmission.
"Community transmission means that traditional epidemiology and contact tracing hasn't been able to identify how the patient came to be infected," De Ligt explained.
"Sequencing the genome and comparing it to other genome sequences from samples both here and abroad can help us understand where it has come from.
"Questions like, have we missed it at the border? Did we miss a close contact? Is it transmitting between or within cities? Should we lock down a certain area?
"As we're seeing fewer cases during the level 4 lockdown, identifying exactly how transmission is occurring is crucial if we are to eliminate the disease."
Rapid sequencing of each case could help identify if it was linked to a certain cluster, to other cases nearby, or from another region.
"For instance, if a Kiwi has recently returned home and tests positive we can know whether they were indeed infected overseas, or have actually been infected after their return," De Ligt said.
"This in turn allows policy decisions to be made to best stop the spread. This will be a powerful tool in helping shape how and when we lower the alert level."
As the number of cases in the country crossed the 1000-mark, scientists have been prioritising the sequencing of certain cases.
"Sequencing capacity across New Zealand in Crown research institutes and universities has been supported by initiatives like Genomics Aotearoa, and we've been actively increasing the numbers of Covid-19 cases we can sequence each week," De Ligt said.
"This involves an interplay of logistics, technical expertise and having enough sequencing machines and reagents."
In the early stages of the crisis, when there was strong data indicating links in New Zealand cases to overseas travel, scientists carried out sequencing of samples to confirm these had been imported infections.
"With our increase in sequencing capacity and lowering of the time between sample collection and sequence we are able to help with suspected community transmission cases where the epidemiological data is less conclusive," De Ligt said.
"Genomics on its own will never be able to identify exactly who infected whom, but it can ameliorate our epidemiological response and is especially adept at saying whether a case is part of or unrelated to the clusters currently circulating in New Zealand."
De Ligt and his colleagues have been sharing their work with the global GISAID Initiative, which acts as a publicly-accessible repository for virus sequence data.
Making the data available gave labs around the world new leads about how the virus, which likely came from an animal, managed to enter human cells.
And ESR's own work had been impressively quick. In accordance with World Health Organisation guidelines on testing initial cases, its team generated a complete RNA sequence within two days.
That was done using protocols designed by the ARTIC Network - another group focused on fast processing of samples from viral outbreak – and with data being integrated through platforms like Nextstrain.
Dr James Hadfield, a Wanaka-based phylogeneticist with Seattle's Bedford Lab, said the level of collaboration between scientists around the world had been unprecedented.
"This has allowed efforts such as Nextstrain.org to present a continually updated view into the movements of the virus around the world, and is a good example where the sum of data from around the world is more informative than any one source in isolation," Hadfield said.
Scientists had even launched a week-long "biohackathon" to work on different aspects of the virus and how to combat it.
Hadfield said the global sequencing effort had been better placed to meet this year's pandemic because of lessons gleaned from the West African Ebola outbreak of 2013-16.
"Many projects and collaborations have been shaped by what was learned there, including the ARTIC network," Hadfield said.
"These techniques have been used to combat many outbreaks since, including the current Ebola outbreak in the Democratic Republic of Congo, Lassa fever in Nigeria, Zika in the Americas and yellow fever, dengue and other arboviruses in South America."
It had also helped that Chinese scientists sequenced and publicly released the genome of SARS-CoV-2 a matter of weeks after the first reported cases.
"This was a huge achievement, and set the stage for the global data sharing effort we are now seeing," Hadfield said.
"This allowed us to identify early community transmission in Washington State, which changed the course of the national response.
"Publicly available ARTIC protocols and software are being used in dozens of countries right now, and in some cases genomes are being generated, shared and analysed through Nextstrain in less than 24 hours. "
But that didn't mean there weren't more lessons to learn.
"We're learning all the time and working to improve the different bottlenecks in the process," De Ligt said.
"Currently there are some delays in samples being referred for whole genome sequencing, partly due to increased testing load on testing laboratories.
"This hampers our ability to get an accurate picture of what's happening right now, which will become crucial as we work to eradicate Covid-19 from our shores."
• Covid19.govt.nz: The Government's official Covid-19 advisory website
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