With all the buzz around CRISPR, the gene-editing technique that has instigated many an ethical debate and one acrimonious patent dispute, it would be easy to mistake it for a recent human invention. It’s not. Bacteria invented CRISPR billions of years ago, as a defense against marauding viruses. The bacteria grab pieces of a virus's genetic material and incorporate these fragments into their own DNA. In doing so, they memorize the identities of past enemies. They can then use the viral sequences to guide their own defensive enzymes.
Now, it seems that some viruses use the same trick. Bernard La Scola and Didier Raoult from Aix-Marseille University have found that some giant viruses have a CRISPR-esque immune system, which they use to defend themselves from other smaller viruses. It seems that the defenders steal the genes of the attackers, and use those ‘memorized’ sequences to tailor their own countermeasures.
This is the latest in a string of discoveries that show how unexpectedly crazy the viral world really is. In the last 13 years, scientists have found giant viruses that outsize bacteria, viruses that parasitize other viruses, and now viruses with immune systems that defend themselves against more viruses. Arms races, it seems, have truly gone viral.
The story began in 1992, when La Scola and Raoult studied amoebas contaminating the water of a cooling tower in Bradford, England. The amoebas were infected by a microbe, which was so large that the researchers initially assumed it was a bacterium. Only later, in 2003, did they realize it was a virus—a huge one, around four times bigger than, say, HIV or the influenza virus. They called it mimivirus.
An entire world of giant viruses soon came to light: Mamavirus in a Parisian cooling tower, Pithovirus in 30,000-year-old Russian ice, and Megavirus and Pandoravirus in Chilean coastal waters. Most of these also infect amoebas, manufacturing new copies of themselves by setting up viral factories in their hosts. And these factories can themselves be corrupted by viruses.
In 2008, La Scola and Raoult noticed that amoebas infected by Mamavirus often carry a second smaller virus. This pipsqueak is a parasite that hijacks Mamavirus’s factories, using them to make copies of itself at the expense of its bigger cousin. When it’s around, the giant virus reproduces slowly, assembles abnormally, and produces daughters that are poorer at infecting amoebas. The team described the smaller virus as a ‘virophage’—an ‘eater of viruses’, a virus that sickens other viruses.
That first virophage was called Sputnik, after the Russian for ‘fellow traveler.’ More were then discovered, including Maverick virus from coastal waters, Organic Lake virophage from an Antarctic lake, and Sputnik 2 found in the inflamed eye of a French teenager.
The latest member of the virophage club is Zamilon, after the Arabic for “neighbor.” Raoult and La Scola found in 2014, and they noticed that it can only parasitize some branches of the Mimivirus family tree. Of the three such branches, one—lineage A—is immune to Zamilon.
Raoult suggested that these giant viruses defend themselves from Zamilon with some kind of CRISPR-like immune system. In other words, they contain stolen copies of Zamilon’s DNA, and using these pilfered sequences, they deploy DNA-slicing enzymes to disable the virophages. “Bernard disagreed, so we competed among ourselves to find the answer,” says Raoult, laughing.
He made three predictions. First, the A-group mimiviruses should contain DNA that matched the Zamilon virophages (which they resist), but not the Sputnik ones (which they don’t). Second, these immunizing sequences would be absent in the other two Mimivirus lineages that were not resistant to Zamilon. Third, the stolen Zamilon sequences would be accompanied by enzymes for unwinding and cutting DNA. All three predictions were true. “The war between giant viruses and virophages is similar to that between bacteria and viruses,” says Raoult.
The giant virus’s defense system, which the team calls MIMIVRE, isn’t exactly the same as CRISPR, but it is very close in form. It’s a wonderful example of convergent evolution, where two groups of living things independently come up with the same solutions to the same problems.
“[Some giant viruses] can get sick from a viral infection and can produce a "immune" response to the infection,” says Chantal Abergel, who has herself discovered several giant viruses and virophages. “Again, this blurs the frontier between viruses and cells and ask for reconsideration of what should be considered as alive.”
Many scientists insist that viruses aren’t alive: They have no autonomy, they don’t metabolize, and they depend on other (living) organisms to reproduce. In the words of one researcher, they exist “on the border between chemistry and life.” Still, the question is far from settled: A recent poll by the Virology Blog, which asked readers about the status of viruses, arrived at an almost perfect three-way split between alive, not alive, and “something in between.”
It’s clear where Raoult stands. “Giant viruses are not ordinary viruses,” he says. He thinks of them just another type of microbe, a group of microscopic living organisms, much like bacteria. They have their own immune system—MIMIVIRE. And they have their own parasites—virophages. Even their parasites have parasites.
In 2012, Raoult’s team found that both Lentille virus (a giant virus) and Sputnik 2 (the virophage that parasitizes it) are parasitized by a selfish piece of jumping DNA. This sequence, which the team called a ‘transpoviron’ can hop in and out of the genomes of both viruses and make new copies of itself. Similar bits of mobile DNA exist within our own cells and those of other living things—another indicator of the blurred boundaries that these giant viruses straddle.
And we’ve only known about this hidden world of giant viruses, virophages, and transpovirons for just over a dozen years. As Raoult once said to me: “If you want to see something really bizarre, you have to look where you didn’t know to look in the first place.”