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At more than 1.5 micrometers long, pithovirus is the largest virus ever discovered — larger even than some bacteria. Many of its 500 genes are unrelated to any other genes on this planet.

At more than 1.5 micrometers long, pithovirus is the largest virus ever discovered.

Chantal Abergel and Jean-Michel Claverie

Carrie Arnold

for Quanta Magazine

Published July 16, 2014

Chantal Abergel and Jean-Michel Claverie were used to finding strange viruses.

The married virologists at Aix-Marseille University had made a career of it. But pithovirus, which they discovered in 2013 in a sample of Siberian dirt that had been frozen for more than 30,000 years, was more bizarre than the pair had ever imagined a virus could be.

In the world of microbes, viruses are small—notoriously small. Pithovirus is not. The largest virus ever discovered, pithovirus is more massive than even some bacteria. Most viruses copy themselves by hijacking their host's molecular machinery. But pithovirus is much more independent, possessing some replication machinery of its own.

Pithovirus's relatively large number of genes also differentiated it from other viruses, which are often genetically simple—the smallest have a mere four genes. Pithovirus has around 500 genes, and some are used for complex tasks such as making proteins and repairing and replicating DNA.

"It was so different from what we were taught about viruses," Abergel said. (Also see "Virus-Infecting Virus Fuels Definition of Life Debate.")

The stunning find, first revealed in March, isn't just expanding scientists' notions of what a virus can be. It is reframing the debate over the origins of life.

Raw Material for Life

Scientists have traditionally thought that viruses were relative latecomers to the evolutionary stage, emerging after the appearance of cells.

"They rely on cellular machinery to help with their replication, so they need to have some sort of primitive cell to make use of that machinery," said Jack Szostak, a biochemist at Harvard University and a Nobel laureate. In other words, viruses mooch off cells, so without cells, viruses can't exist.

But some scientists say the discovery of giant viruses could turn that view of life on its head. They propose that the ancestors of modern viruses, far from being evolutionary laggards, might have provided the raw material for the development of cellular life and helped drive its diversification into the varied organisms that fill every corner of the planet.

"These giant viruses are the perfect example of how a world of simple viruslike elements could evolve into something much more complex," said Eugene Koonin, a computational biologist at the National Institutes of Health. Koonin described his theory for a viral origin of life in a paper published in June in the journal Microbiology and Molecular Biology Reviews.

He and others are accumulating evidence that viruslike elements spurred several of the most important stages in the emergence of life: the evolution of DNA, the formation of the first cells, and life's split into three domains—Archaea, bacteria, and eukaryotes. Archaea and bacteria are all unicellular organisms, and eukaryotes emerged after an ancient fusion event between an archaeon and a bacterium.

The predominant theories for the origin of viruses propose that they emerged either from a type of degenerate cell that had lost the ability to replicate on its own or from genes that had escaped their cellular confines.

Giant viruses, first described in 2003, began to change that line of thinking for some scientists. These novel entities represented an entirely new kind of virus. Indeed, the first specimen—isolated from an amoeba living in a cooling tower in England—was so odd that it took scientists years to understand what they had.

They first assumed the amorphous blob was a bacterium. It was roughly the same size as other bacteria and turned a brilliant indigo when stained with a chemical that adheres only to some bacteria. Try as they might, however, even a team of crack British microbiologists couldn't grow the organism in the lab. Because many types of bacteria are difficult, if not impossible, to grow in the lab, the scientists didn't think much of it and put the sample in the freezer.

Nearly a decade later, a curious graduate student in England took samples of the organism to Didier Raoult, a microbiologist in France who specialized in difficult-to-grow bacteria. He looked at the blob, only this time with a powerful electron microscope. As luck would have it, Abergel and Claverie were collaborating with him on another project. They immediately recognized the organism's viruslike shape—imagine a 20-sided die, with each face a triangle—even though the specimen was several times larger than any virus either had seen.

When Abergel and Claverie looked at the virus's genome, they found it contained nearly a thousand genes—as many as some bacteria. The scientists named it mimivirus, for MImicking MIcrobe virus, because amoebae appear to mistake it for their typical bacterial meal.

Giant, Yet Undetected

Abergel and Claverie suspected that giant viruses abound in the natural world but go undetected because of their size. They took samples of amoebae-filled water from nearly every locale they visited. In two samples—one from a stream in Melbourne, Australia, and one taken off the coast of Chile—they found an even bigger virus growing in amoebae, which they named Pandoravirus and described in a study in the journal Science last year. (Related: "Biggest Virus Yet Found, May Be Fourth Domain of Life?")

"We repeated every experiment ten times because this virus was so weird," Abergel said. "We kept thinking we had made a mistake."

With a staggeringly high number of genes, approximately 2,500, pandoravirus seemed to herald an entirely new class of viral life. "More than 90 percent of its genes did not resemble anything else found on Earth," Abergel said. "We were opening Pandora's box, and we had no idea what might be inside."

Then, several months ago, they found pithovirus, which dwarfs even pandoravirus in size and possesses genes equally as strange. These bizarre genes immediately led scientists to speculate on the origin of giant viruses. Since pithovirus's genes were so different from anything else scientists had seen, it seemed possible that the ancestors of giant viruses had evolved early in life's history.

This idea, however, conflicted with the generally accepted view that viruses didn't evolve until much later. Giant viruses provide the perfect opportunity to study how viruses evolved, since they are only distantly related to other viruses and afford an as-yet-unseen perspective on virus evolution. But when exactly did viruses emerge—before or after the development of cellular life? (See "Ancient Virus DNA Gives Stem Cells the Power to Transform.")

The Virus World

Koonin is firmly in the "before" camp. According to his theory, dubbed the Virus World, the ancestors of modern viruses emerged when all life was still a floating stew of genetic information, amino acids, and lipids. The earliest pieces of genetic material were likely short pieces of RNA with relatively few genes that often parasitized other floating bits of genetic material to make copies of themselves. These naked pieces of genetic information swapped genes at a primeval genetic flea market, appropriating hand-me-downs from other elements and discarding genes that were no longer needed.

Over time, Koonin argues, the parasitic genetic elements remained unable to replicate on their own and evolved into modern-day viruses that mooch off their cellular hosts. The genes they parasitized began to evolve different types of genetic information and other barriers to protect themselves from the genetic freeloaders, which ultimately evolved into cells.

The Virus World Theory is closely related to the RNA World Theory, which says life first evolved as small pieces of RNA that slowly developed into complex DNA-carrying organisms. The Virus World Theory agrees that life's genetic material began as RNA. But it differs by arguing that the ancestors of viruses evolved before cells.

Supporters point to a few lines of evidence. First, the diversity of viruses far exceeds that found in cellular life.

"Where diversity lies, origin lies," said Valerian Dolja, a virologist and plant cell biologist at Oregon State University who collaborates with Koonin. (See more pictures of viruses.)

According to this perspective, if viruses developed from cells, they should be less diverse because cells would contain the entire range of genes available to viruses. It's a recurring theme in evolutionary biology: One of the reasons we know humans originated in Africa is that genetic diversity among residents of that continent is much greater than it is anywhere else. If this pattern of diversity is true for humans, Dolja said, there's no reason it can't also be true for viruses.

Viruses are also more diverse when it comes to reproduction. "Cells only have two main ways of replicating their DNA," said Patrick Forterre, a virologist at Paris-Sud University. "One is found in bacteria, the other in Archaea and eukaryotes." Viruses, on the other hand, have many more methods at their disposal, he said.

Forterre suggests that viruses evolved after primitive cells but before modern cells. Some of the viruses that infect the three different domains of life share several of the same proteins, suggesting that they may have evolved before life diverged into these three branches. (Read blog post: "An Infinity of Viruses.")

Forterre has yet to identify any of these proteins in cellular life, except in a snippet of DNA that was clearly the result of the insertion of viral genes.

"Viruses had to exist before the last universal common ancestor of all life on Earth," Forterre said.

Alive or Not?

Giant viruses have further blurred the definition of what it means to be alive. According to the standard definition, traditional viruses are not alive because they lack the machinery to replicate their genes and must steal those found in their cellular hosts.

But giant viruses seem to lie somewhere between bacterium and virus—alive and not. They have some genes involved in replication, which indicates that they may have once been free-living organisms that devolved into viruses.

Some researchers say that means they deserve their own branch on the tree of life, creating a fourth domain that would leave the other three—Archaea, bacteria, and eukaryotes—largely intact. Also supporting the idea of a giant viral branch is their genetic weirdness: Giant viruses have unusual genes that aren't found on other branches of the tree.

Despite their unusual genes, giant viruses have been grouped into a larger family of viruses known as the nucleocytoplasmic large DNA viruses, which includes smallpox. Giant viruses are much more complex than smallpox, so scientists initially thought they evolved later than their more traditional viral cousins. But more recent work indicates that these viruses also evolved very early in the history of life.

Gustavo Caetano-Anolles, a bioinformatics specialist at the University of Illinois, Urbana-Champaign, traced the evolutionary history of proteins found in several giant viruses in a 2012 study in the journal BMC Evolutionary Biology.

His work shows that these viruses "represent a form of life that either predated or coexisted with the last universal common ancestor," the most recent organism from which all other organisms on Earth are descended. If giant viruses are as old as Caetano-Anolles calculated, the implications are staggering. It means that a giant virus or one of its ancestors existed before other types of life and may have played a major role in shaping life as we know it. This could mean that viruses are one of the dominant evolutionary forces on this planet and that each organism has a deep, viral past. (Read "Small, Small World" in National Geographic magazine.)

Szostak agrees with Koonin and others that viruses have been a powerful evolutionary force and that they evolved earlier than scientists previously thought. However, he distinguishes between parasitic genetic elements (small pieces of genetic material that use other pieces of genetic material to make copies of themselves), which he agrees were likely present before the development of cells, and true viruses, which can't exist without cells.

"Whenever you mix a bunch of small RNA molecules together, you get a bunch of parasitic sequences that aren't good at anything except making copies of themselves faster than anything else," Szostak said. For these sequences to become similar to modern viruses, they need to parasitize a living cell, not just another strand of RNA.

Dolja disagrees, saying that cells could not have evolved without viruses. "In order to move from RNA to DNA, you need an enzyme called reverse transcriptase," Dolja said. "It's only found in viruses like HIV, not in cells. So how could cells begin to use DNA without the help of a virus?"

Abergel and Claverie, however, believe that viruses emerged from cells. While Forterre and collaborators contend that the unique genes found in giant viruses are a sign that they evolved before modern cells, Abergel and Claverie have a different explanation: Giant viruses may have evolved from a line of cells that is now extinct.

According to this theory, the ancestor of giant viruses lost its ability to replicate as an independent life-form and was forced to rely on other cells to copy its DNA. Pieces of these ancient cells' genes survive in modern mimivirus, pandoravirus, and pithovirus, which would explain the unique genes found in this group. "Life didn't have one single ancestor," Claverie said. "There were a lot of cell-like organisms that were all competing, and there was one winner, which formed the basis for life as we know it today."

It's unlikely the debate over when and how viruses first evolved will ever be settled—that's the nature of trying to answer a question whose history has faded with time. But Abergel and Claverie continue to believe that giant viruses will be key to any answers that emerge.

The pair hunts for even larger, stranger iterations, which they hope will reveal not only the evolution of giant viruses, but perhaps of all viruses.

"Everywhere we look, we find giant viruses," Claverie said. "Either we're brilliant, or these things are everywhere."

Follow Carrie Arnold on Twitter and read her posts on National Geographic's Weird & Wild.

This story originally appeared in Quanta Magazine, an editorially independent division of SimonsFoundation.org, whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

12 comments
Joseph Ferri
Joseph Ferri

I've long suspected we've been looking through the wrong end of the telescope. Homo sapiens, my a_ _!

Adolfo Gomez Cala
Adolfo Gomez Cala

Consider the probabilistic hurdles that must be overcome to construct even one short protein molecule of one hundred amino acid in length. (A typical protein consists of about 300 amino acid residues, and many crucial proteins are very much longer.)

First, all amino acids must form a chemical bond known as a peptide bond so as to join with other amino acids in the protein chain. Yet in nature many other types of chemical bonds are possible between amino acids; in fact, peptide and non-peptide bonds occur with roughly equal probability. Thus, at any given site along a growing amino acid chain the probability of having a peptide bond is roughly 1/2. The probability of attaining four peptide bonds is: (1/2 x 1/2 x 1/2 x 1/2)=1/16 or (1/2)4. The probability of building a chain of 100 amino acids in which all linkages involve peptide linkages is (1/2) raised to 99 or roughly 1 chance in 10 raised to 30.

Second, in nature every amino acid has a distinct mirror image of itself, one left-handed version or L-form and one right-handed version or D-form. These mirror-image forms are called optical isomers. Functioning proteins tolerate only left-handed amino acids, yet the right-handed and left-handed isomers occur in nature with roughly equal frequency (why not?). Taking this into consideration compounds the improbability of attaining a biologically functioning protein. The probability of attaining at random only L-amino acids in a hypothetical peptide chain 100 amino acids long is (1/2) raised 100 or again roughly 1 chance in 10 raised 30. The probability of building a 100 amino acid length chain at random in which all bonds are peptide bonds and all amino acids are L-form is, therefore, roughly 1chance in 10 raised to 60.

Moreover, functioning proteins have a third independent requirement, the most important of all;their amino acids must link up in a specific sequential arrangement just as the letters in a meaningful sentence must. In some cases, even changing one amino acid at a given site can result in loss of protein function. Moreover, because there are twenty biologically occurring amino acids, the probability of getting a specific amino acid at a given site is small, i.e. 1/20. (Actually the probability is even lower because there are many non-proteineous amino acids in nature). On the assumption that all sites in a protein chain require one particular amino acid, the probability of attaining a particular protein 100 amino acids long would be (1/20)raised to 100 or roughly 1 chance in 10 raised to 130. We know now,however, that some sites along the chain do tolerate several of the twenty proteineous amino acids, while others do not. The biochemist Robert Sauer of M.I.T has used a technique known as “cassette mutagenesis” to determine how much variance among amino acids can be tolerated at any given site in several proteins. His results have shown that, even taking the possibility of variance into account, the probability of achieving a functional sequence of amino acids in several known (roughly 100 residue) proteins at random is still “vanishingly small,” about 1 chance in 10 raised to 65—an astronomically large number. (There are 10 raised to 65 atoms in our galaxy). Doug Axe of Cambridge University has used a refined mutagenesis technique to measure the sequence specificity of the protein Barnase (a bacterial RNase). Axe’swork suggests that previous mutagenesis experiments actually underestimated the functional sensitivity of proteins to amino acid sequence change because they presupposed (incorrectly) the context independence of individual residue changes. If, in addition to the improbability of attaining proper sequencing, one considers the need for proper bonding and homochirality, the probability of constructing a rather short functional protein at random becomes so small (no more than 1 chance in 10 raised to 125) as to appear absurd on the chance hypothesis. As Dawkins has said, “we can accept a certain amount of luck in our explanations, but not too much".

In othr words, my friends, I woudn't bet to the life-by-chance-only horse even if my life were at stake.

Have fun.

Adolfo Gomez Cala
Adolfo Gomez Cala

Great! It only needs to be explained where the giants viruses came from. Good Luck!

Jim A.
Jim A.

That should get the neocons going.

Donald Round
Donald Round

Amazing! I wonder where prions will turn out to be on the evolutionary ladder of life?  

Harmeet Aurora
Harmeet Aurora

This just fuels my belief that most people are just one big Herpes virus! ;)


Irwin Busk
Irwin Busk

If you were to back off a ways,  the earth would possibly look like a life form,  with the human parasites swarming  all over it, and growing fast.

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