What Was The First Virus?

Rome. At its peak in the 2nd century AD, the empire dominated 5 million square kilometres from the Atlantic coast of Iberia all the way to the Persian Gulf. And at its heart was the Eternal City. Cramped, bustling, filled with the colours, sounds, smells and fluids of a thousand cultures poured into one. Marketplaces saw fine silks from the Far East traded alongside artisan chain mail from Gaul and jars full of blood red wine from the Roman heartland. Free men, scholars and slaves of every creed and colour rubbed shoulders in the streets, the hub of a giant, multicultural empire. The perfect place for disease to proliferate. The ultimate, super-spreader city. So it was in the summer of 166 AD that famed Roman physician Galen found himself battling an enemy much deadlier than any barbarian horde. Limping home from distant Parthia in the east, three legions had returned with a cruel gift from those far-off lands. Their skin covered with sores and pustules. They burned with fever and the entire camp stank of loosened bowels. Death hung in the air. The plague quickly spread. It struck indiscriminately, affecting Rome's citizens equally, with cruel indifference to position or stature. Galen tried to treat the afflicted. Some recovered, their skin permanently scarred and their bodies broken. Many weren't so lucky. He studied the dead and dying. He probed their wounds, searching for some common factor, some hidden cause. But even he, the most accomplished physician in the city, failed to find the agent of such destruction. The plague continued for years and from the empire's glorious centre outward it spread, entire cities and towns wilting under its attack. Three years after its arrival in Rome, the Emperor Lucius Verus finally succumbed, and some eleven years later his co-ruler Marcus Aurelius also died with the very same fever and blistered skin. Galen witnessed it all, but was helpless to stop its seemingly limitless spread. By 180 AD, 70 million souls had died, totalling more than a quarter of the Roman Empire's entire population. Galen was a visionary of his age, but he was trapped in the second century and could do little more than document the pandemic as it unfolded. Had he possessed the scientific understanding and equipment of a 20th century doctor, he could have identified the sickness as smallpox. This vicious disease was only conquered in 1980, some 1800 years after the devastating Antonine Plague. It was caused by a virus, a mere particle less than one hundredth of the width of a human hair. This of course was not the first time viruses had changed the course of history, and it wouldn't be the last. Had Galen possessed the understanding of our 21st century scientists, he could have peered into the genes of his fellow citizens to see the legacy of viruses written into our very DNA. For what Galen did not know, what he could not have known, was that his Parthian gift had been evolving hand in hand with the life it ravaged for billions of years, potentially since before the very beginning of life itself. To understand the origins of the enigmatic viruses Galen battled 1800 years ago, we must first unravel what exactly his silent enemy was. And the first to even get close to this mystery was the Russian botanist Dmitry Ivanovsky. At the time, a plant disease was threatening one of the most valuable luxury exports of North and South America, tobacco plants. In an effort to find the cause, Dmitry had taken the leaves of diseased plants and crushed them, reducing them to a liquid extract. He then passed this extract through a solid porcelain filter, with pores so small that even the smallest known bacterium couldn't squeeze through. But to Ivanovsky's surprise, this processed, filtered extract still had undiminished potential to infect new tobacco plants. Whatever was causing the tobacco mosaic disease, it was smaller than bacteria. What on earth could be so small, he thought, and still contain the essence of such coordinated destruction? It would take another 40 years of scientific advancement before the virus was actually seen for the very first time. If we could shrink our bodies down a million fold so that we were just a micrometer tall, we would be able to see with our naked eyes the tiny viral particles responsible for such terrible diseases as smallpox, hepatitis and AIDS. There are about 100 million more viruses on earth than there are stars in the universe. Each less than a thousandth of a millimeter in size, they are denizens of a rich and varied nanocosmos. Each minuscule particle is intricately crafted, as distinct in form and function as the macro-sized lifeforms they infect. In shape alone, there are tiny rods, smoothed and spiked spheres, angular dodecahedra and upright spidered forms that bear more resemblance to interplanetary probes than any lifeform we know. They range in size from a mere 20 nanometers to relative giants as large as a bacterium. Giant pythoviruses cruise this nanocosmos, leviathans searching for amoeba to infect. Ebola is a grotesque knotted snake locked in a permanent rictus of torture, while tiny bacteriophages seem the most complex of all, with features that resemble legs, a head and a deadly injecting syringe. Within these alien structures are genetic molecules, similar in construction to our own double-stranded DNA or single-stranded RNA, but shorter, simpler, more naked and exposed. These are unlike the cells that make up the bodies of every living thing on Earth. They are little more than a hard protein shell around a fragment of DNA, and each one is unique, containing its own assortment of genes that tailor it to a particular host, whether human, animal, plant or microbe. A virus floating freely through the air is inert, and a virus unsuited to our body's chemistry is harmless. Only when a viral particle encounters its preferred host will its spring into action. With compatible chemistry, it will be able to insert its genetic molecule fragment into an unwitting cell to hijack its living processes to reproduce itself. Some simply use the protein machinery suspended in the cell's cytoplasm to blindly reprint the virus's genes for packaging and shipment back out of the cell. But others are more tenacious. These so-called retroviruses insert their DNA fragment directly into the DNA of their host. In reality, the viral nanocosmos is made visible only with the most cutting-edge technology, and modern scientists are still working to understand how these seemingly simple agents can bring about such suffering, and how they can be conquered. So, we have seen the enemy, the first step to understanding its origins. But even now, a fundamental question remains unanswered. What is a virus? And are they even alive? Answering this question calls into doubt our understanding of what separates life from non-life on Earth, and elsewhere in the cosmos. Classic definitions are taught in schools that living things all have the independent ability to move, grow, reproduce, sense their surroundings, seek nutrients, extract energy from them, and excrete waste. By this scheme, viruses are certainly not alive. They do not grow, they don't have any metabolic processes, and they are utterly reliant on a host for reproduction. They are parasites, as lifeless as dust without the spark of life stolen from other living things. There are, of course, exceptions though, as always. In England in 1992, a new kind of was found in a cooling tower. For 10 years, scientists thought it was a kind of bacteria because of its large size. But high-resolution imaging revealed that it was, in fact, a virus of unprecedented size and complexity. A leviathan floating amongst minnows, nearly 10 times as large as its cousins. They named it Mimivirus because it mimicked living bacteria so closely. These mimiviruses contained more than just a DNA fragment, they also had enzymes and other machinery inside their shells. Not quite enough for independent living, but much more than we had previously thought inert viruses capable of processing. Although the vast majority of viruses may not be classically alive, they are still undoubtedly of life. The fact that they have the same genetic molecule and the same biochemistry that makes them seamlessly compatible with living cells must elevate them above the inanimate world, even if they don't fully deserve a place in the animate one. Some scientists have suggested that we revise our classification of life purely to include these potent organic nanoparticles. Perhaps they deserve their own branch on the tree of life, rooted at the base next to the origin of the domains of bacteria and eukaryotes. But one thing is clear. To understand the virus's place among life on earth, we need to try and trace their history through geological time. To know what they are, we have to understand how and when they began. But finding the unimaginably small among the unimaginably ancient is a problem modern scientists are only just beginning to tackle. And the solution may not lie in the rocks beneath our feet, but within our very DNA. At the southeastern tip of England, the green fields of Kent meet the blue of the English Channel in a flash of white. The White Cliffs of Dover tower over the modern-day port. They are a welcome sight to British travellers returning from the south and were immortalised in a wartime song as a beacon of hope for better things to come. And yet these cliffs might just be the remnant of a series of deadly pandemics that took place 65 million years ago. They are made of chalk, a form of limestone or calcium carbonate made up of tiny grains as fine as powder, compacted into solid rock. Every single one of these grains is a fossil. A tiny mineralised scale that once formed part of a spherical shell around a single-celled alga called a coccolithophore. When magnified hundreds of times, these individual coccoliths are intricate disks of surprising complexity. Combined in their many trillions, the disks are the sole constituent of cliffs more than 100 metres tall. These hopeful, pure white cliffs are nothing more than an immense graveyard, the remnant of death on a spectacular scale. Coccolithophores, protected in their calcium carbonate spheres, are green algae that float in the surface waters of the oceans, soaking up the sun to power photosynthesis inside their cells. But coccolithophores, like all life on Earth, are not immune to viral infection. There is a virus, tiny in comparison to the already miniscule algal cells, that can penetrate the protective sphere and penetrate the photosynthesising cell. The boneyards left behind by these algal pandemics are mere sprinklings of coccolith scales, among other sediments that wash over the ocean floor. But at the end of the Cretaceous period, some 70 million years ago, coccolith graveyards accumulated over tens to hundreds of thousands of years. Algae bloomed and died, bloomed and died, over and over again, thickening the layer of chalk mud until it was some half a kilometre thick. And this is still the case, millions of years later. Viruses are constant adversaries of every living thing, and we are doomed to grapple with them in the future, as we have done in the distant past. But viruses are capable of more than destruction, and our shared history is far more complex. The constant threat of viral infection has in fact been a major driver of evolution. When an infecting virus damages cells and brings about disease, then a species' survival depends on it being able to adapt, to weather the storm or eject the offending particle. In this way, the immune system has evolved as a defence in animals, and been incrementally improved over millions of years. But this only works for so long, in response to the immune defence viruses themselves evolve and adapt. It is a military arms race writ small, with both sides improving their advances until the very nature of the warfare evolves. But there is another, unexpected role that viruses have to play in the evolution of life. These tiny, inanimate particles behave like genetic messengers between otherwise unrelated organisms. Produced in one hijacked cell, a virus will be released into the world, where it can infect another, possibly belonging to an entirely different species. The genes that the viruses carry are shared between the infected, giving them all access to unique traits, without having to evolve them from scratch, without their own genetic code. The retroviruses, which reproduce by inserting their genes into the DNA of their host cells, inadvertently gift the host with the instructions for new features, which may just turn out to be beneficial. Scientists think that a retrovirus that infected early mammals gave them the instructions for making a new kind of protein, which eventually led to the creation of the placenta during pregnancy. In 1990, the Human Genome Project was an outrageous and ambitious effort by scientists all over the world to read the Encyclopedia of Human DNA. It was no small task. They were trying to determine the order of some 3 billion base pairs, or characters in the Instruction Manual of Life. Had these been written on actual pages, they would have filled several hundred volumes. But just 13 years after it began, after revolutions in genetic techniques and But the work was only just beginning. Although they now had the ordered characters of DNA in hand, it would take another international and multidisciplinary effort to interpret what these characters meant. The results trickled in over the early years of the 21st century. One of the most shocking revelations was that just a tiny fraction, 4% of DNA, actually corresponded to the genes that determine our features. The rest was something of a mystery. For a long time, termed junk DNA, now we think a lot of it controls when the gene is turned on or off. Recently, cutting-edge science has revealed that some 8% of the total originated in viruses. Specifically, retroviruses that smuggle their genes into the unknowing host. Normally, the retroviral redraft only happens in body cells, and can be cloned and copied when the host is alive, but disappears when the infected organism dies. But if a retrovirus happens upon a sex cell, an egg or a sperm destined for a new generation, then its code is carried forward, to be preserved ever more within the genes of the descendants. There's just a miniscule chance of this happening, but over millions of years, the retroviral inventory in our cells has gradually grown. And now, there is twice as much virus in us, than there is us. This could be the key to tracing viruses back to the very beginning. Paleontologists probe ancient rocks for the fossil remnants of living things, and microfossils of tiny bacteria have been found dating to some 3.5 billion years ago. But there is no prospect of finding viral fossils preserved in rocks. It is hard enough for viruses to be isolated and imaged accurately in modern samples, let alone those crushed and cooked inside rocks, ravaged by time. So, searching for viral fossils becomes a subject instead for geneticists, who compare through time with the molecules of life. By sequencing the genomes of humans, animals, plants and bacteria, geneticists can trace the history of viral infections through time. If a viral sequence is shared by an entire group, then it's likely that the group's ancestor was the one who was infected first. Recently, a group of scientists identified a molecular fossil in our genome that was also shared by about 25 other mammals, including aardvarks, marmosets and bats. But this viral fossil seemed to be randomly scattered among the different types of mammals, it was as notable in its absence as in its presence. This told an intriguing story of not one ancient infection, but of many. A series of viral epidemics that crossed species back and forth, infecting unsuspecting animals for some 15 million years. Although we don't know for sure what the virus did to these animals, what is certain is that its genes are now forever part of our story, just as viral genes seem to have been a part of the story of life. Perhaps, since life itself has been around, and their origins are as indistinct as the origin of life. So, in search of the first virus, it helps to try and consider how viruses came to be. How can something obtain some of the features of life, but never all of them? In 2002, just a few short years after the Human Genome Project published the Encyclopedia of Life for the first time, Eckhart Wimmer and his team at Stony Brook University in New York achieved something that had previously only been the stuff of science fiction or conspiracy. They created a virus from scratch. Like Dr. Frankenstein, they used the advanced and seemingly magical genetic techniques that the Genome Project had pioneered to stitch together DNA sections in the precise order to make a simple monster, a poliovirus, related to the wild polio that crippled adults and children in the middle of the last century. Something like Wimmer's breakthrough must have happened naturally in the biological world sometime in the history of life. The result is the viral nanocosmos we see today, and the record of their DNA in our cells. Only, the first viruses must have arisen without the 21st century tools at a geneticist's disposal. As for how this viral shadow life can arise naturally, scientists still aren't sure, but there are a couple of theories. The first is of progressive virus evolution. There is a strange phenomenon in most eukaryotic cells in which small sections of genes can move, jumping from one area in the genome to another. It is as if the first page in a book could occasionally jump from the beginning, to the end, to somewhere in the middle. If these sections of DNA acquired the ability to move in and out of a cell too, with the help of a little protein protection, then they would have had the same transmissible qualities of a virus. From moving between the pages of a single book, these progressive genome fragments could choose any location in an entire library. This explanation best fits the characteristics of retroviruses, which have this compatibility with their host genomes and the unique ability to rewrite their DNA. But not all viruses work in this way. A second possible theory is one of regression, where living cells gradually lose their metabolic machinery, leaving only the basic genes to be passed on to future generations. By dispensing with their intercellular proteins, the regressive cell loses its independence. It must rely on another life form to supply the energy and processing power for reproduction. It becomes a parasite. We know this has happened with bacteria in the past. The bacterial cells that were engulfed to become mitochondria and chloroplasts inside early eukaryotic cells are now so diminished that they could no longer survive on their own. Could this have been the root of viruses too? Looking at the giant mimiviruses with basic proteins alongside the genetic molecule, it is easy to imagine them as having once been alive and independent. The scant evidence left within most viruses means there's little else to decide between a progressive and regressive origin. Perhaps they are both correct, with different types of viruses arising independently in different ways throughout history. But there is another intriguing possibility. Viruses are singly adapted for one of the most fundamental features of life. That of reproduction. And we know that the very first cells, which originated in the Archean oceans some three and a half billion years ago, must have been capable of this too. Even before the first cells, there must have been a genetic molecule capable of storing and replicating genetic information for future generations, and the iterative evolution of biological metabolism. A replicating molecule without a biological metabolism was probably one of the earliest steps in the evolution of life from non-life. And today we find replicating molecules without a biological metabolism all around us. In viruses. In theories of the origin of life, a single-stranded genetic RNA molecule could have acted as its own replication machinery. It is no great leap to imagine single-stranded RNA viruses behaving the same way. In the absence of living cells to hijack. And so, in this virus-first hypothesis, the viruses didn't break free of life or regress from more advanced living cells, but preceded life itself. They could have been a vital step in the origin of all life on Earth. Once true life as we understand it surrounded itself with a cell and built a self-sustaining metabolism, then the viral branch on the tree of life diverged. The earliest viruses themselves evolved, building protective protein shells and devising more efficient ways of replicating themselves using machinery borrowed from the other branch of life. In this way, true life and the viral shadow life were destined to be eternally intertwined. Viruses there before the first cells and then alongside the first cells, ready to hijack and infect. It's an enticing theory, but we may never know for certain. An unimaginable gulf of time lies between the modern nanocosmos and the earliest virus. But the clues that we can find, from Galen's view of the unstoppable Roman plague to the geneticists' viral fossils written into our very DNA, suggest that viral infection is, and perhaps always has been, a fundamental part of life on Earth. You've been watching the entire history of the Earth. Like and subscribe and leave a comment to tell us what you think, and we'll see you next time.