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Expert opinion: why studying the origins of SARS-CoV-2, its variants and relatives matters

22 December 2021

Microbial Genomics
Genome Sequence Machine Esr
Genome Sequence Machine Esr

Professor Mike Worobey is used to whodunnit stories when it comes to viral origins.

The University of Arizona sleuth’s most recent paper in the journal Science puts layers and layers of data into the animal origin, or zoonosis, hypothesis of the SARS-CoV-2 virus.

The temporal and spatial patterns of early Covid-19 cases places it firmly within, and adjacent to, the Wuhan wet markets.

While, conspiracy theories will no doubt continue, the evidence is solid that this is a recent spillover from animals. Should we be surprised?

The answer is a categorical “no”.

We have seen spillovers before, not a few times, but lots. We should not be surprised. 

In Professor Worobey’s own words on the topic he “scienced it pretty hard” and the answer was as clear as it can be under the circumstances.

Sure, more data would be nice, but as he wrote in a pre-pandemic publication on Zika, “systematic pathogen surveillance is within our grasp, but is still undervalued and underfunded relative to the magnitude of the threat”.

As we write this piece, the Variant of Concern (VOC) named Omicron is spreading across the globe.

Where did this VOC originate and why does it matter? How is it mutating?

Is there anything we can reasonably do to turn down the VOC tap that seems to visit us with concerning regularity? 

The more than six million genomes generated for Sars-CoV-2 provide an intimate picture of the ancestral family tree since December 2019 in Wuhan - we know which virus is related to which, including when each viral lineage (or VOC) both lived and died.

It truly is an international tour de force of collaboration that countries share their data for the benefit of humanity – the release of Omicron data from Africa is a case in point.

This real-time window into the genetic ‘soul’ of the virus is a perspective we have never had previously – without it we would be struggling to understand, and respond to, infection waves.  

Speaking of Omicron, just a few short weeks ago, if you had asked any researcher who studies Sars-CoV-2 where the next variant would evolve from, you would have got a clear consensus; it will be related to Delta.

You would have got excellent odds, had you bet on a long-lost viral relative from 2020 reappearing and displacing Delta in a tsunami of cases.

It is like a ghost from our past disappeared into the jungle last year and came back to life armed with a new game plan and an extreme makeover.

The jungle analogy might not be as far from the truth as you might think.

There are, currently, three hypotheses as to how Omicron might have surprised the planet.

  1. We simply missed it for over a year in our surveillance – Omicron evolved in southern Africa for this period but decided to never leave its home-base.
  2. Omicron developed within an immune compromised individual(s) where it learnt how to evade the immune system in what is, virologically speaking, a perfect training ground.
  3. The virus made a jump into an animal host in 2020, in what is termed a reverse zoonosis, learnt a few new tricks with its spike, and then jumped back into humans in late 2021.

 We may never know which of these is correct, it is difficult to find the smoking gun in any forensic analysis that extends back in time.

Hypothesis A is highly unlikely given our genomic surveillance across Africa, and while many researchers favour hypothesis B the recent finding that Omicron seems surprisingly well adapted to replicating in rodents has caused many to evaluate hypothesis C. 

 We know that studying viruses in animals is essential to predicting pandemics, including development of risk factors at the wildlife-human interface.

What’s more, new genomic sequencing platforms mean that we now have the ability to interrogate viruses in wildlife with speed and precision that was not possible a decade ago.

While searching for viruses, and their variants, in animal populations may be like searching for the needle in the proverbial haystack sometimes it is worth the effort.

The lack of samples from wildlife in Wuhan has hampered insights into pandemic origins.

Likewise, the lack of wildlife screening for Sars-CoV-2 may have resulted in the Omicron blind spot we now sit in. 

 Be it birds or bats, rodents or racoon dogs, studying the viruses in animals that live with us and around us is part of what Professor Worobey was referring to when he said systematic pathogen surveillance is within our grasp.

Simply studying what is already in humans is not the solution and certainly not what one would call pandemic preparedness.

Far from an academic exercise, the study of virus in other species is vital.

The rationale behind this statement is, in part, related to how viruses evolve.

 Viruses are experts in the game of genomic cut-and-paste; a process known as recombination.

While not often discussed in the media, we have seen recombination occur with Sars-CoV-2.

A scenario of a person, or more accurately one of their cells, infected with two different VOC’s can make a “hybrid”.

If one were to catastrophise, this hybrid might be more transmissible or virulent.

It might also be less virulent. Given the global prevalence finding a Delta-Omicron hybrid would not be surprising.

Covid-19 aside, the importance of screening wildlife for viruses is vital as the genes contained in a seemingly unimportant species may enable us to build better understanding of risk as well as the factors that control how, where and when viruses to jump to new hosts. 

 For example, maybe the high prevalence of coronaviruses in bats and the susceptibility of pangolins or racoon dogs - and a few other taxa as well - to coronavirus means these animals should not be co-located.

We could even extend rules and regulation at a landscape scale with the co-location of pigs and poultry (flu) or pigs and bats (Nipah virus).

Perhaps regulating the necessity of rodent control around ferret farms? Land use adjacent to some wildlife habitats could be more scrutinised and/or monitored.

At its heart, the Covid-19 pandemic was triggered by a failure to monitor and regulate the legal and illegal trade in wildlife.  

 In time we hope a virological surveillance system up gets up and running - it will require a level of global cooperation that has a good chance of success if the science is put in front of politics.

In the meantime, through necessity, we are forced to watch Omicron genomes displace Delta genomes in a Game of Thrones-style shootout.

As we write this piece, there are eight Omicron genomes in Aotearoa New Zealand, and the family tree is shown in the figure below.

The genetic variation we see in this tree is due to the huge number of viral replications that occurs in each host - think many billions.

When the huge number of replications is multiplied by the number of cases you can start to grasp why this “tricky” virus remains a moving target. 

The Covid-19 pandemic has taught us many lessons with regard to microbial evolution and disease emergence.

Indeed, we may only be part way though the prerequisite “Pandemic 101” course that has already exposed us to some brutal examinations.

Far from having a human-centric perspective of viruses, we advocate that it is time for the global community to explore the world around us a bit more - it is certainly within our capability and grasp.

Here’s hoping our response moving forward is calibrated to the risk.

There is a saying that “when biosecurity works then nothing happens” - and few would argue that a dose of pandemic “nothingness” would be welcome right now.

 *Professor Michael Bunce works for ESR, which provides genomic services for New Zealand, and also provides science advice for the Ministry of Health. He has previously published studies with Professor Worobey on the origins of HIV-1.

 *Dr Jemma Geoghegan is an adjunct at ESR and a senior lecturer at the University of Otago. She regularly analyses genomic data for decision makers and has received funding via the University of Otago to study the evolution of viruses.