The genius of genomics: The revolution that helped NZ quash Covid-19

It’s played a starring role in New Zealand’s clever response to the Covid-19 crisis – and been three decades in the making. Science reporter Jamie Morton looks at the genomics revolution – and its potential to change Kiwi lives.

Another stray case of Covid-19 was the last thing Aucklanders wanted to hear.

The infected person had been out and about in the central city, where tens of thousands of people live and work – but it what wasn’t known that really caused worry.

Was this a one-off case that could be connected to an earlier-identified cluster?

Or was it the worst-case scenario of the first detected infection of a large outbreak that had been spreading silently for weeks?

Two Fridays ago – Friday the 13th, as some pointed out at the time – a city and a nation braced for another lockdown.

But dread soon gave way to relief.

“The news that I have to share is positive,” Health Minister Chris Hipkins told that afternoon’s media conference, before confirming the case was indeed linked to the known cluster.

“That direct link means that the new case doesn’t point to an unknown border incursion that could be spreading – and it also means the risk of wider, unseen spread is less likely.”

What the public hadn’t seen was the flurry of work that had gone on in an ESR wet laboratory in Porirua.

A small team of scientists had worked late into the night to match the genetic signature of the latest case to another existing one.

But the power of genomics – which had effectively given authorities the satisfaction they needed to not confine more than a million people to their homes again – had been showcased once more.

Much of New Zealand’s stunningly successful response to the pandemic has been underpinned by it.

And it wouldn’t have been possible had Covid-19 emerged three decades ago, before the dawn of the genomics revolution.

Solving the jigsaw

We can think of a whole genome as a box of jigsaw pieces, all of which make up the genetic puzzle of any organism on the planet.

Within our own box is 22 paired chromosomes, along with a 23rd that sorts our sex.

It’s formed as a double helix of DNA, or deoxyribonucleic acid, and packs about 30,000 genes, along with three billion chemical bases that help hold the strands of DNA together.

Even the SARS-CoV-2 virus that causes Covid-19 has its own jigsaw puzzle. But it’s different in that its comprised of ribonucleic acid, or RNA, so is single-stranded rather than double-stranded like DNA.

Unsurprisingly, it’s much less complex than us: it contains just 30,000 bases, making up 15 specific genes.

Scientists piece these puzzles together through a process called sequencing – or figuring out the order of bases in a genome, then assembling them at once to get a complete picture of an organism’s DNA.

That’s different to genetic engineering, which involves tweaking or changing the assembly of genes.

Three decades ago, getting the full blueprint of a human being was considered a mind-boggling feat.

But that’s just what a huge effort, dubbed the Human Genome Project, set out to achieve.

Launched on October 1, 1990, the project pulled together scientists from around the world, given the task was far too great for one nation alone to pursue.

It took just two years for the team to build a framework with which they could use to begin assembling the genome.

A major facet of it was work carried out in tandem, that explored the sometimes-thorny ethical, legal and social implications of what the scientists were doing.

Another was a commitment to make data available to researchers everywhere as soon as it was generated, meaning scientists could jump on it immediately and start looking for sequences for mutations that might cause disease.

Like any mammoth undertaking, the scientists first focused on developing and testing technology they were using to put the puzzle together.

Species with smaller genomes proved great candidates for practice runs.

The first of them was a bacterium known to cause serious illness in young children; its genome, measuring just 1.8 million bases long, was published in 1995.

The scientists moved on to a popular brewer’s and baker’s yeast and notorious bacteria E. coli, whose genomes were revealed in 1996 and 1997 respectively.

Next came the world’s first full sequence of an animal genome: a tiny nematode worm whose genome nonetheless stretched to 100 million bases.

The first whole human chromosome – and our smallest, at 49 million bases – was sequenced in 1998, followed by the first plant, thale cress, in 1999, and the fruit fly – at 139.5 million bases – in 2000.

By the turn of the century, scientists had created a sturdy platform for building genomes.

In 2001, they unveiled the first draft of our genome, and also sequenced the genomes for rats, mice and rice, stuffed with some 430 million bases.

When the project formally ended in 2003 – a year before the complete human genome was revealed – it had transformed the face of science, and all inside its planned 15-year, US$3 billion timeframe and budget.

It remains the world’s largest collaborative biological project, and a triumph to rival the Moon landing and the pioneering of penicillin and electricity.

The door to understanding countless diseases and human evolution had been unlocked.

Still, the completed human genome didn’t fit that of each of us – the genome of any individual is unique – but a small number of people involved.

By sequencing each chromosome, scientists put together something of a mosaic, representing the general make-up of a human being.

Although New Zealand wasn’t involved in the project as a country, individual Kiwi researchers here and overseas were.

And by the time it had delivered the tools needed to rediscover those species important to us, local scientists seized on them.

New Zealand played a part in unravelling the genome of the honey bee – which proved the last which drew on only the techniques used in the project – and later, the sheep.

Out of Kiwi labs came the blueprints for springtails, wasps and manuka, to name a few – while native species like moa and kiwi have been completed overseas.

The revolution continues

The speed of sequencing a genome, and the cost of doing it, has been slashed dramatically in 20 years.

“In 2003, the sequence of a human genome took 13 years and $2.4 billion,” said Professor Peter Dearden, a leading Otago University geneticist who heads New Zealand’s umbrella institute for the field, Genomics Aotearoa.

“Now we can sequence a human genome in a matter of days for about US$300, and the price and speed is dropping all the time.

“We are facing an oncoming tsunami of genome data, which requires the smartest data scientists and informaticians to surf.”

This wave of data is, however, changing our world.

There are now countries running 100,000 cancer patient genomes through their systems every year, with goals of refining these down to the relatively small number of driver mutations behind most tumours.

A range of new state-of-the-art, compact DNA-sequencing machines can now quickly decode a human genome.

One Mars Bar-sized device called the MinION, now being used in labs around New Zealand, can analyse a portion of our DNA in just a few hours.

It works by reading genetic sequences from a DNA sample as it travels through about 500 tiny pores in the device, with the data fed into a laptop via USB, allowing scientists to work with only around 16,300 bases.

While the ultimate goal of the Human Genome Project was to construct what’s now called the “reference genome”, scientists have branched out from it to explore the immense variation in biology.

That variation is crucial, because it might be related to health or disease in humans, or production traits in agricultural plants and animals, or disease susceptibility in our conservation species.

Dearden said Kiwi scientists have now built up their own expertise in data generation, and stitching together genomes.

“These days we are not just interested in a single reference genome – though many are being produced in New Zealand currently – but also in the genomes of whole populations,” he said.

“We can use this information to support improved health in human populations, or more efficient production in agriculture, or to make better decisions in conservation management.”

The reality was, he said, if New Zealand didn’t work out how genomics could benefit its own unique needs – nobody would for us.

“We are also using genomics to understand and better manage fish stocks – and we’re even doing this for kākāpō, helping the Department of Conservation with management decisions about this critically endangered species.”

Through the kakapo125+ project, the genomes of every remaining bird were sequenced by 2018, revealing genetic insights that are now helping deal with everything from infertility and disease to ageing, relatedness and dwarfism.

In recent years, genomics has also been used to look at whole ecosystems – a technique called metagenomics.

Microbes live all around – and even on – us. By sequencing genomes of the communities of these microbes, we can better understand the environments we live in, or even the environment of ourselves, our guts and our skin.

Using genomics to identify and understand the microbial world feeds into better managing our health and our environment.

As the coronavirus pandemic has shown, it’s been invaluable in countering outbreaks.

In New Zealand’s first wave of Covid-19, scientists sequenced the genomes of 649 separate cases to reveal nearly 300 different introductions from different parts of the world.

Sequencing proved just as crucial in the August outbreak, helping pick apart Auckland community cases – effectively informing the response to the cluster in real time.

It’s even driven new advances here, with ESR scientists pioneering a new assay allowing them to construct whole genomes out of virus samples missing many of the RNA fragments usually needed.

A smarter future

Before the Covid-19 spotlight, Dearden said genome sequencing had been a little invisible, or seen through the lens of film-makers dystopian visions.

“It can even be treated a bit suspiciously, as our genome sequence is very personal and as such, may not be something we want to give up lightly,” he said.

“Despite this, large numbers of people have had DNA tests through or 23andMe, who, while they don’t sequence your genome, do generate large amount of genomic data to provide not-very-useful information about ancestry or disease status,” he said.

“Genome sequencing has huge potential to improve our lives, but it has also the potential to be used in ways we are uncomfortable with.

“It is more than time we had public discussion about the use of this technology here.”

Dearden said genomics was improving our health already, showing us where tumours might be sensitive to drugs, identifying people who react badly to medicines, and helping us track infectious disease.

In the future this will extend to public health, allowing us to identify variation in the genome that, in particular environments, could underpin health or disease.

One example is a trail-blazing project that’s used the latest sequencing technology to analyse the DNA of more than 600 Kiwis, including a large group of adults considered at risk of obesity.

Around one in three New Zealand adults are now obese – including nearly half of Maori and 68 per cent of Pacific Island people – and health researchers have labelled the rising rates a crisis.

But while an increase in obesity rates in recent years has been put down to lifestyle factors such as poor diet and a lack of exercise, the genetic predisposition to obesity, particularly among Maori and Pacific Island populations, has been less understood.

Successfully employing genomics to monitor Covid-19 in New Zealand may have also paved the way for tracking other outbreaks across all species, including in cattle disease M. bovis, which has already cost authorities nearly $350m to manage.

Elsewhere in agriculture, genomics has transformed sheep and cattle breeding, and is being rolled out as a way to support breeding to bees and fish and crop plants.

“Being able to understand and tightly control the breeding of plants and animals will allow us to better fit our primary production to the environment – increasing efficiency is absolutely critical to managing resources and to the future of our planet,” Dearden said.

“In the face of climate change, this information will be crucial to ensure the profitability of our primary production.”

Metagenomics, particularly, has the power to change the way we manage our environments.

It could be used as a way to track changes in the environment caused by pollution, to tell us what crops to grow where, to help us protect the health of plants and animals, and to trace pathogens in human populations.

“New Zealand needs to be part of the rapid global advances in genomics and informatics research to ensure it stays ahead and gains value from emerging knowledge, and so that its researchers can be of a world standard,” Dearden said.

“New Zealand, therefore, needs cross-disciplinary effort and a knowledge-sharing environment to build its core computing infrastructure and bioinformatics expertise, which will drive genomics research development specific to our own needs.”

That was what Genomics Aotearoa – a Government-funded collaborative platform of nine universities and crown research institutes – was striving toward, he said.

“Genomics is complex and can even be daunting, but if genomics researchers can work with people in a collaborative, trustworthy and open way, then trust can be built around these technologies.”

New dad's hospital wait inspired a breakthrough

When Dr Miles Benton’s first child was born prematurely and required a lumbar puncture for suspected viral meningitis, he and his wife faced a 48-hour wait for blood test results.

As he sat in hospital, the ESR scientist pondered whether there was a faster way to get them – and if there wasn’t, what could he do to help improve things?

That moment led to a breakthrough Benton made with the help of international colleagues, and a small but powerful single-board computer.

It has the potential to make genomic science faster, easier and more accessible, with implications in everything from conservation to medicine.

Benton first began looking for a solution to his problem in a small, Mars bar-sized device to complete real-time analysis of long DNA or RNA fragments.

As it turned out, there were others, just like him, working on these issues and more using Oxford Nanopore Technologies’ MinION device.

“This tech enables people to get results and act faster than ever before to protect health and communities, something that falls right into our wheelhouse at ESR,” he said.

“I began working on an issue some months ago that has been slowing down efforts for true portability. The challenge was pairing the MinION with fast enough compute and small enough to be powered off batteries.”

Currently, the MinIONs do not have built-in graphics processing units (GPUs), preventing them from completing what’s known as live-base calling.

In other words, you still need to plug them into a computer in order to get your results – but traditional computers with GPUs are relatively expensive, less portable and need regular recharging.

A lot of back and forth with other scientists finally led to a breakthrough.

“We were able to get live base-calling going on the device,” he said.

“I publish my work online through a blog so anyone who is interested can see and contribute. I had no idea anyone was even following what I was doing until I started to make some progress.

“People then started talking and had ways to solve issues based on their experiences, that’s true science in action – the sharing of information to solve collective issues.

“There is nothing like the excitement of troubleshooting an issue at 3am with someone in Switzerland and another person in Italy, and then getting it working and seeing real results almost instantaneously. It’s incredibly powerful and humbling.”

Building on this work, Benton and his team have been able to assemble a $1200 portable kit, weighing less than 2kg.

“The beauty of it is that we have strung some technologies and off-the-shelf products together, including a solar panel and an external battery, to mean that a person could conceivably do this without access to mains power,” he said.

“The applications for this kind of portable, real-time technology are immense.”

ESR was now actively looking for projects where this kind of technology can be explored, both with community and other scientists.

“I am far from the only one using these devices,” he said.

“Currently the MinION has been used in Africa in mobile vans to track viruses such as Ebola and Zika. It has also been taken into the rain forest and people have made makeshift labs set up to sequence and discover new species.

“It has even been used to sequence DNA in the International Space Station. What we have achieved here is making it more portable, affordable and accessible.

“This tool is only limited by the imagination of those who use it – it falls upon us to find new ways of using it in different contexts.”

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