Are Viruses Actually Alive?

Over the past two years, the SARS-COV2 virus, better known as COVID-19, has wreaked havoc around the globe, infecting more than 346 million people, causing 5.58 million deaths, shutting down entire industries and nations, and completely changing our way of life. It is humbling to think that humanity has been brought to its knees by a pathogen so small it is dwarfed by most bacteria – and more humbling still when you consider that said pathogen might not even be alive. Unlike other disease-causing agents like bacteria, protozoans, and fungi, viruses occupy a hazy region between life and non-life, with which side of the line they fall on depending entirely on who you ask. It is a fierce and ongoing debate, one which raises one of the most fundamental questions in biology: what even is “life” anyway? So, is a virus a life form? Let’s dive in shall we?

To understand whether viruses are alive or not, we must first understand what a virus even is. While viral diseases like smallpox, rabies, polio, and influenza have been with us since the dawn of humanity, it is only very recently that scientists came to understand the peculiar pathogens which cause them. Following the development of the germ theory of disease by Robert Koch, Louis Pasteur, and others in the mid-19th Century, scientists embarked on a quest to hunt down and isolate the bacterial agents responsible for every known disease. Among these was Tobacco Mosaic Disease, an affliction which stunts the growth of tobacco plants and causes their leaves to develop a mottled, “mosaic”-like pattern. In 1892, Russian botanist Dmitri Ivanovsky ground up the leaves of infected tobacco plants and passed the sap through a porcelain filter whose pores were too small to let even bacteria through. He then used the filtered sap to inoculate uninfected plants. To his surprise, the plants still developed the disease. Ivanovsky concluded that the disease was caused by some kind of chemical toxin which could pass through the filter, but did not pursue the matter further.

Six years later, Dutch microbiologist Martinus Beijerinck repeated Ivanovsky’s experiments and confirmed his puzzling results. However, he also took the experiment a step further. After infecting one plant, Beijerinck ground up its leaves, filtered the sap, and used it to infect another plant, and so on and so forth. If the infectious agent was a toxin, he reasoned, then its potency would be reduced as it was diluted from plant to plant. But no matter how many times he transferred the disease, it remained as infectious as before. At first, Beijerinck simply assumed that the infectious agent was simply an incredibly small bacterium, but no matter how hard he tried, he could not get it to grow on a nutrient medium – the standard method for culturing bacteria in the laboratory. It was also impervious to alcohol, which killed nearly all known bacteria. Stranger still, the agent, whatever it was, only seemed to grow and multiply in the presence of other dividing cells. Baffled as to what this agent could be, Beijerinck dubbed it contagium vivum fluidum, or “contagious living fluid” and later “filterable virus”, after an old word meaning “toxin.”

Over the following decades, scientists would discover many more viruses using the porcelain filter method, including apththovirus, the cause of foot-and-mouth disease, in 1898; and the yellow fever and rabies virus in 1932. But the first major breakthrough in understanding what viruses actually were came in 1935, when American chemist Wendell Stanley determined that the tobacco mosaic virus was a particle, not a fluid like Beijerinck had hypothesized, and was composed entirely of protein. Stanley even managed to purify the virus particles into needle-like crystals, which could be stored indefinitely on the laboratory shelf without losing any of their infective potency. This discovery sent shockwaves through the scientific community, as a 1940 New York Times article reported:

“When Dr. Wendell Stanley of the Rockefeller Institute’s Princeton station crystallized the virus which produces the mosaic disease of tobacco, there was a great hullabaloo among the biologists. And rightly so. Were these crystals alive? Apparently no more so than diamonds, glass, sand or other crystals with which we are familiar. Yet when virus crystals were put on a tobacco leaf, the mosaic disease spread like a slow fire over a whole field just as if it had been infected by living bacteria.”

 Stanley’s discovery, which won him the 1946 Nobel Prize in Chemistry, seemed to deal a death blow to the centuries-old doctrine of vitalism, which held that organisms contained some sort of vital essence or divine spark which made them come alive. The chemical hypothesis of life, by contrast, held that life was simply a chemical process like any other, and Stanley’s discovery that an apparently inert protein particle that could multiply and spread like a living organism seemed to confirm this.

But many mysteries remained. In the same year as Stanley’s discovery, the invention of the electron microscope allowed viruses to be directly observed for the first time and revealed why they had eluded microbiologists for so long. Most virus particles are on the order of 100 nanometers across, 10-100 times smaller than the average bacterium and too small to be seen using a regular light microscope. But this did not explain how a mere protein particle could behave as though it were alive, yet be unable to grow in a laboratory environment. In 1926, American microbiologist Thomas Rivers proposed an explanation, stating in a presentation before the Society of American Bacteriology that:

“Viruses appear to be obligate parasites in the sense that their reproduction is dependent on living cells.”

 In other words, viruses did not reproduce on their own via cell division like bacteria, protozoans, fungi, and other microorganisms, but instead hijacked the molecular machinery of other living cells to produce more virus particles. But how did viruses accomplish this hijacking? As it turned out, a major piece of the puzzle was still missing. As later research by Wendell Stanley revealed, the tobacco mosaic virus was not, in fact, composed only of protein, but also of ribonucleic acid, or RNA. In the 1930s and 40s, a great scientific debate raged over the agent of heredity which allowed genetic traits to be passed from one generation of organisms to the next. While the laws of heredity had been discovered by Czech monk Gregor Mendel in the 1860s and refined by American biologists Thomas Hunt Morgan and Hermann Muller in the 1910s, the specific molecule which encoded and transferred genetic information remained unknown. While some scientists suspected nucleic acids like RNA or its cousin deoxyribonucleic acid or DNA to be this agent of heredity, most believed the more likely culprit to be proteins, which were far more complex than nucleic acids and could thus store more genetic information. Viruses would play a key role in determining which hypothesis was correct.

In 1952, American bacteriologists Alfred Hershey and Martha Chase conducted a series of now-classic experiments using T2 bacteriophages, viruses that infect the bacterium E. coli. At this point it was known that viruses inject one part of themselves into the host cell, leaving the other part behind. But the question remained: was it the nucleic acid or the protein which was injected? To find out, Hershey and Chase first cultured a batch of viruses in a cell medium tagged with radioactive sulphur, which would only be incorporated into the protein of the virus. The next batch of viruses was cultured in radioactive phosphorus, which would only be incorporated into the nucleic acid. Both virus batches were then allowed to infect clean E. coli cells, and the resulting cultures spun in a centrifuge to separate the infected cells from the discarded, non-coding part of the viruses. When Hershey and Chase measured the radioactivity of the infected cells, they discovered that those tagged with phosphorus were radioactive, while those tagged with sulphur were not. This confirmed that it was the nucleic acids, not proteins, which the viruses injected into the cells. Subsequent work by scientists such as Rosalind Franklin, James Watson, and Francis Crick would go on to reveal the structure and function of DNA and RNA, starting a genetic revolution that is still shaping the world to this day.

Today, it is understood that all viruses consist of two basic components: a strand of nucleic acid like DNA or RNA encased a protein coat or capsid – or, as British biologist Sir Peter Medawar eloquently put it:

“A piece of bad news wrapped up in a protein.”

 Viruses come in all shapes and sizes, ranging from 27 nanometers for the porcine circovirus to 1.5 micrometers for Pithovirus, and from long and tubular like the Tobacco Mosaic Virus to spherical like Coronaviruses. In addition to their protein coats, many viruses also incorporate a lipid envelope derived from their host’s cell membrane. The life cycle of a virus begins when it enters its host and makes contact with its cell membrane. If the cell is susceptible to said virus, then the virus latches on and, like a miniature syringe, injects its genetic material along with a number of enzymes into the cell’s cytoplasm, leaving the capsid behind. Once inside, the genetic material begins the nefarious process of taking over the cell’s metabolic machinery and converting it from an independent organism to a tiny biological factory with a single purpose: to produce more virus particles. Viruses accomplish this hijacking in several different ways. In DNA viruses, the virus’s genetic material takes the place of the cell’s own DNA, and uses the cell’s own enzymes to transcribe this invasive genome into messenger RNA or mRNA. This mRNA is then read by cellular organelles known as ribosomes, which uses its genetic instructions to assemble amino acids into proteins. Only instead of the regular proteins normally used by the cell to keep itself running, the ribosomes now produce components for new viruses. RNA viruses, on the other hand, contain mRNA that is directly read by the ribosomes, skipping the DNA transcription step entirely. And yet a third variety of viruses, known as retroviruses, pull off an even neater genetic trick. Retroviruses, which include HIV, contain an enzyme called reverse transcriptase, which takes the virus’s RNA and incorporates it into the host cell’s own DNA. This embedded viral genome, known as a provirus, can remain dormant within the host’s genome for a long time, invisible to the immune system and passed along from cell to cell as they divide and multiply. They can then spontaneously reactivate, causing the cells to start producing viruses again. This can make infection by retroviruses very difficult to combat. But the importance of retroviruses goes far beyond human disease. A full 8% of the human genome consists of proviruses acquired throughout our long evolutionary history, and as we shall see, these genetic hitchhikers have had a significant and under-appreciated impact on the development of life on earth.

Once the new virus particles are assembled, they must then escape the host cell. For many viruses that infect bacteria and other single-celled organisms this is accomplished via the lytic cycle, in which the cell membrane is ruptured or lysed, killing the host cell and releasing the new generation of viruses into the environment. However, as killing every cell a virus encounters would quickly lead to the death of the host and the viruses with it, most viruses instead exit the cell via either exocytosis or “budding,” passing through the cell membrane without rupturing it. But whatever the process, the end result is the same: the newly-assembled viruses are released into the environment, ready to infect new cells and start the whole process over again.

Now that we know what viruses are and how they reproduce, let us return to our original question: are viruses actually alive? The answer, as with so much in biology, depends on how exactly one defines life. Unique among the sciences, there is no firm consensus within biology as to what exactly it is that biologists actually study. While at first glance the question of whether something is alive or not might seem straightforward, throughout history a concrete, testable definition of life has eluded even the greatest scientific and philosophical minds, with the common consensus essentially boiling down to “we’ll know it when we see it.” But as the lack of such a definition did not prevent biologists from carrying on with their work, for many years the subject remained a mere philosophical curiosity. However, as humanity began to explore the cosmos and search for life on other planets, the question “what is life?” suddenly became a much greater priority.

Over the years, various scientists have attempted to draw up lists of properties unique to living organisms, such as this one from the NASA website:

“[Living organisms] have the ability to take in energy from the environment and transform it for growth and reproduction. Organisms tend toward homeostasis: an equilibrium of parameters that define their internal environment. Living creatures respond, and their stimulation fosters a reaction-like motion, recoil, and in advanced forms, learning. Life is reproductive, as some kind of copying is needed for evolution to take hold through a population’s mutation and natural selection. To grow and develop, living creatures need foremost to be consumers, since growth includes changing biomass, creating new individuals, and the shedding of waste.”

However, many of these properties are also exhibited by non-living systems. Crystals, for example, can spontaneously organize into incredibly complex and ordered shapes, self-replicate and transfer this internal order from crystal to crystal, and even move in response to external stimuli. Similarly, a dark stone can convert solar energy into thermal energy and then into kinetic energy by heating the air around it, while radioactive elements can spontaneously turn nuclear energy into thermal energy. This definition even breaks down when applied to certain biological systems. For example, prions, the agents responsible for Bovine Spongiform Encephalopathy – better known as Mad Cow Disease – are even simpler than viruses, consisting of rogue mis-folded proteins devoid of any genetic information. Nonetheless, prions can mutate, spread from host to host, and multiply, though not by passing on genetic information but rather by causing adjacent proteins to mis-fold in a deadly chain reaction – and for more on this, please check out our previous video The Gruesome Tale of the Laughing Death Epidemic.

 A more sophisticated set of properties unique to living organisms was set forth by Austrian physicist Erwin Schrödinger, best known for putting hypothetical cats in hypothetical boxes. In his 1944 book What is Life? Schrödinger remarked upon:

 “…an organism’s astonishing gift of controlling a ‘stream of order’ on itself and thus escaping the decay into atomic chaos.”

 In other words, living organisms appear to defy the 2nd Law of Thermodynamics, which states that in a closed system, entropy – variously defined as disorder or energy which cannot be used to perform useful work – always increases. In the face of natural forces which are constantly tending towards greater disorder, organisms not only manage to maintain a high degree of internal order and complexity, but to maintain said order over multiple generations with very little loss of fidelity. Of course, organisms do not actually violate the Second Law since they are not closed systems. Rather, they are semi-bounded systems, closed off enough from the outside world to maintain internal order but permeable enough to allow this increase in order to be counterbalanced by a decrease in order outside the organism – for example through the release of waste heat. Nonetheless, these observations allowed Schrödinger to postulate that such a semi-bounded structure was essential to the functioning of living organisms. More importantly, he further postulated that in order to accurately transfer their internal order and complexity to subsequent generations, organisms required some form of “code script” containing instructions for building that particular organism. This prescient prediction would of course be vindicated less than a decade later by the discovery of the structure and function of DNA.

In the wake of Schrödinger, scientists like British biologist John Maynard-Smith suggested that the fundamental property of life was its ability to undergo Darwinian natural selection, in which heritable traits which increase an organism’s reproductive capacity are selected for and preferentially passed on to subsequent generations, allowing species to gradually evolve over time. Eventually this notion was combined with previous definitions to produce the so-called “NASA definition of life”, which states that:

 “Life is a self-sustained chemical system capable of undergoing darwinian evolution.”

 On the second count, viruses certainly fit the bill – as the rapid mutation of COVID-19 into multiple variants clearly demonstrates. But it is on the first part of the definition that the argument for viruses being alive stumbles, for unlike other organisms viruses are unable to replicate in the absence of other living cells. Without a host cell’s molecular machinery to hijack, a virus is just an inert bit of protein and genetic material. Thus, according to Gerald Joyce of the Salk Institute:

 “According to the working definition, a virus doesn’t make the cut.”

But for not being alive, viruses certainly play an outsized role in the natural environment. While it is impossible to know for sure, biologists estimate that there are some 1031 viruses in the world, a number so mind-bogglingly large that if laid end-to-end, these viruses would stretch some 200 million lightyears – well past some of the farthest known galaxies. Viruses are found in every environment on earth and infect every known organism, though the vast majority are benign and do not cause harmful illnesses. Nonetheless, they have had a tremendous impact on the evolution of life on earth, particularly via the reverse transcription of viral genes into the host’s DNA. For example, blood oranges exist thanks to a viral gene called Tcs2, which in response to cold weather switches on a gene called Ruby that gives the fruit its distinctive deep-red hue. Closer to home, an ancient viral gene called ERVW-1 is responsible for the development of a fused-cell structure in the human placenta called a syncytiotrophoblast [“sin-site-ee-oh-troh-foh-blast”], which is vital for the transfer of nutrients to the developing embryo. Thus, all of us owe our very existence to a virus that infected an African ape millions of years ago.

For this and other reasons, certain scientists believe that the NASA definition of life is overly narrow, and should be expanded to include borderline cases like viruses. Among these is French microbiologist Patrick Forterre of the Pasteur Institute, who argues that:

“Life and living processes are simply names for complex evolving forms of matter that are now present on our planet.”

 Forterre conceives of viruses not simply as assemblies of protein and nucleic acids but as organisms with two distinct phases in their life cycles: the inert virion or virus particle, and the “virocell”, the living cell which has been taken over by the virion and converted to producing more virions. In Forterre’s model, the virocell is contrasted with the “ribocell”, the regular, healthy form of the host cell, the difference between the two being:

“Whereas the dream of a normal cell is to produce two cells, the dream of a virocell is to produce a hundred or more virocells.”

Thus, according to Forterre, the virion is to the virocell what a seed is to an oak tree, and viruses no different from any other parasite that depends upon its host to grow and reproduce; they are simply more dependent than most.

Other scientists argue that any attempt to rigorously define life is inherently unproductive, as it might prevent us from recognizing as-yet undiscovered exotic forms of life on earth or other planets. As Carol Cleland, a philosopher of science at the University of Colorado explains:

“Definitions tell us about the meanings of words in our language, as opposed to telling us about the nature of the world. In the case of life, scientists are interested in the nature of life; they are not interested in what the word “life” happens to mean in our language. What we really need to focus on is coming up with an adequately general theory of living systems, as opposed to a definition of “life.”

 Despite its amazing morphological diversity, terrestrial life represents only a single case. The key to formulating a general theory of living systems is to explore alternative possibilities for life. I am interested in formulating a strategy for searching for extraterrestrial life that allows one to push the boundaries of our Earth-centric concepts of life.

 On the other hand, I don’t think that defining “life” is a very useful activity for scientists to pursue since it is not going to tell us what we really want to know, which is “what is life.” A scientific theory of life would be able to answer these questions in a satisfying way…[and] do the same for [fringe cases]. Merely defining “life” in such a way that it incorporates one’s favourite non-traditional “living” entity does not at all advance this project.”

 And so the debate rages on, with nearly every biologist being firmly convinced that the matter has already  been settled one way or the other. All we can say for sure is: given their impact on the past, present, and future of life on earth, alive or not, viruses deserve nothing but our utmost admiration and respect.

If you liked this article, you might also enjoy our new popular podcast, The BrainFood Show (iTunes, Spotify, Google Play Music, Feed), as well as:

Expand for References

Zimmer, Carl, Are Viruses Alive? The Royal Institution, November 25, 2021, www.youtube.com/watch?v=Tryg5UCp6fl

 

Racaniello, Vincent, Virology Lectures 2021 #1: What is a Virus? January 12, 2021, www.youtube.com/watch?v=jX3MhWWi6n4

 

Campbell, Neil, Biology, The Benjamin/Cummings Publishing Company, Inc, Menlo Park, California, 1987

 

Nurse, Paul, What is Life? The Royal Institution, December 19, 2019, www.youtube.com/watch?v=_zSUo2wP4l

 

Life’s Working Definition: Does it Work? NASA, https://www.nasa.gov/vision/universe/starsgalaxies/life%27s_working_definition.html

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