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Why ancient pandemics may hold the key to our future survival

Our DNA bears the scars of an arms race that humanity has been fighting for millions of years.

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Twenty-five thousand years ago, the first elements of modern humanity were beginning to emerge in Europe. One of the earliest known settlements, near the Dyje river in what is now the Czech Republic, was founded; a place where people lit fires, spun thread, wore clothes and caught fish on hooks. Ceramics had just been developed, and people began to form clay or to carve other materials into likenesses of men, women and deities. Humans had reached an important new stage on the journey that had begun two million years earlier with the sharpening of the first flint knife.

Then, in large numbers, they began to fall ill.

How can we say that a virus caused a pandemic, 20,000 years before the beginning of recorded history? David Enard, an evolutionary biologist who works at the University of Arizona, says the scars of ancient epidemics, and the history of our long and ceaseless war with viruses, are written in our DNA. Finding out what caused them may help us to predict the next pandemic.

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Enard’s work involves searching human genomes for evidence of ancient epidemics. It has led him to believe the current outbreak is one in a series of hundreds or even thousands of epidemics and pandemics that have afflicted humans through every moment of our evolution. In 2016, while he was at Stanford University, Enard showed that around 30 per cent all the adaptive mutations in our genome – a third of human evolution – has been in response to viruses.

Even within the span – vanishingly brief, in evolutionary terms – of recorded history there are examples such as the Black Death, caused by the bacterium Yersinia pestis, the devastating influenza pandemics of 1889 and 1918, and the plagues that ravaged the Greeks, Romans, Aztecs and many others. “But if you start thinking in terms of hundreds of thousands of years of evolution… it leaves a lot of time for hundreds or even thousands of pandemics to have occurred”.

Enard finds the evidence of these ancient plagues by looking at the effect they had on our evolution. Early people would have had some knowledge of medicine, but this would have done nothing to prevent or cure a new infectious disease. The only defence they had was that which they carried in their genes.

“Mutations are usually harmful,” Enard explains, “but when a pandemic happens, it could be that some individuals… have mutations that actually make them resistant against the infection.”

There are several ways that genes could confer an advantage. One kind of mutation could be a change in the immune system, which would “make the immune cells of these people more able to control the virus early on, so that the virus does not multiply so much”. The RSAD2 gene that most mammals possess, for example, causes cells to produce a substance that prevents viruses from copying their genomes and replicating; it is thanks to this gene, among many others, that we do not succumb to the trillions of viral particles that cover our skin, infest our noses and digestive systems, and wash through our blood.

The other way in which our genes could adapt to a virus would be by controlling the immune response. In the case of Covid-19, for example, the virus provokes a reaction – a “cytokine storm” – that is so strong that it seriously damages or even kills the body it was supposed to protect. But in some cases, says Enard, mutations have allowed people to “build a more controlled immune response” to viruses, allowing them to endure their own defences for long enough to recover.

How does he know which virus was seen off by a particular mutation? When a viral particle, or virion, comes into contact with a human cell, its proteins interact physically with the proteins of the cell. It is, says Enard, as if the human cell is a factory, and the virus breaks in, takes specific pieces of equipment – proteins – and reprogrammes them to make copies of itself.

“We happen to know, thanks to the hard work done by virologists, which specific human proteins interact with which specific viruses,” he explains. “There are around 20,000 human proteins in human genomes in total. And we know for example from work that has been published very recently that Covid-19, for example, seems to interact with about 300 of those 20,000 proteins.”

If Enard and his fellow researchers see a mutation that is relevant to these 300 specific proteins, it suggests that the mutation was relevant to a coronavirus. And if this mutation can be seen to have spread across many generations of people, over thousands of years, it suggests that this gene may have been carried by people who survived a coronavirus pandemic in the prehistoric world.

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To figure out when such a pandemic happened, Enard uses population genetics, a science that he compares to the building of family trees, but on a vast scale. By analysing the genomes of large numbers of people from around the world, and the differences between them, population genetics tools can build genealogies that “reconstruct the genealogy of those people on the very deep timescale” – drawing trees of relations that extend tens of thousands of years into the past.

When Enard combines the data from population genetics with the mutations that have allowed people to defeat viruses, there emerge “sweeps” – peaks in the data that signify where a mutation became important to survival. Looking at RNA viruses – which include coronaviruses, ebola, zika and others that we know have caused new infectious diseases – he has seen signs of very significant sweeps between 300 and 900 generations back. Somewhere around 10,000 and 25,000 years ago, RNA viruses “imposed a strong pressure on the ancestors of a specific human population at the time that the advantageous mutations emerged”.

Evolutionary biologists use phrases such as “selective pressure” or “evolutionary pressure” to describe factors that make it more difficult to pass on one’s genes. This does not always mean death – Enard explains that evolution can be counterintuitive, in that even very small advantages can “trigger strong and rapid natural selection” – but in the case of a disease, the strongest selective pressure is exerted when the pathogen kills everyone who isn’t immune to it. This is the sombre truth of evolution. “When we talk about adaptation, it sounds like some something positive, right? But it happens because there's something very bad happening.”

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What’s striking about talking to David Enard is how much he seems to dislike viruses. A police officer or a war historian will often speak about their subject with a certain respect for the ingenuity of the criminal, or the significance of the conflict. But for Enard, it seems that viruses represent nothing more than two million years of suffering. A third of human evolution has been geared towards simply not being killed by “inert bags of molecules” that he does not even consider to be alive. The arms race between humans and viruses is, he says, “very much a zero-sum game. There’s nothing positive about it.”

If anything, humans may have been selected by viruses to survive with traits that we would not otherwise have wanted. The survivors were not superior people, but those with damaged proteins, faulty equipment in their cells that the viruses could not use. Viruses have not helped us to evolve; they have held us back.

Perhaps for this reason, Enard sees his work as growing in importance; not as an immediate reaction to the current global pandemic, but in helping us combat the next pandemic, which will inevitably occur.

Viruses are by far the most numerous biological entities on Earth; a single teaspoon of seawater can contain ten million virions. Despite their tiny size, their combined weight is more than three times that of the planet’s human population. The Global Virome Project has estimated that 500,000 species of virus have the potential to become zoonotic – to jump, as the novel coronavirus did last year, from animals to humans.

It would be hopelessly naive to imagine that the epidemics of the last few hundred years are all we have to worry about. “We are still very, very far from having sampled even a tiny proportion of all the viruses that are out there lurking in different species,” says Enard. “As we sequence more human genomes and the genomes of other species, we will be able to learn more and more about ancient epidemics, not only in human evolution, but in the evolution of many other species potentially. And this could tell us a lot about which viruses are driven by pandemics in the past and, as a consequence, which viruses we should be suspicious about.”

In 1964, when the Scottish virologist June Almeida discovered a previously unknown type of virus causing respiratory disease in chickens, her findings were dismissed as simply “bad pictures” of influenza. It was not until she produced a clearer photograph of the coronavirus in 1966 that it was recognised.

Even then, scientists, doctors and politicians had little reason to think these viruses could cause a pandemic. If only they could have asked our ancestors, 25,000 years ago, about the true potential of these tiny particles. This research may yet give them the means to do so.

Will Dunn is managing editor of the New Statesman.  

This article appears in the 29 May 2020 issue of the New Statesman, The peak