Leap day, giant viruses, and gene-editing

2016 is a leap year. A leap year, or intercalary year, is a year with an extra day inserted to keep pace with the seasons. In the Gregorian calendar this falls every four years on Feb 29th.

On Leap Day this year a wonderful piece of science was published about an equally rare part of nature – giant viruses. Just as a leap day adds the essential nuance to a human devised system making it accurately reflect the physical world, this study bolsters our knowledge of the machinations of the biological world.

And the implications are potentially profound. Giant viruses, namely the mimiviruses, turn out to harbour a gene-editing system.

Gene-editing is being compared to the moon landing, is a strong contender for a Nobel prize, has been used to reverse the cancer of a toddler, and brings with it potentially dystopian visions of designer babies and eugenics.

The gene-editing story started not in the field of medicine, or even human genetics, but in the field of environmental microbiology. Gene-editing systems, now used by humans to artificially modify organisms, such as pet micro-pigs, are used as immune systems in bacteria.

The most popular form of gene-editing, CRISPR-CAS, was originally identified, compared across microbes (Archaea and Bacteria) and given a name by Francisco Mójica, a microbiologist, in the 1990s. He noted that Japanese researchers had observed repetitive CRISPR sequences in E. coli as early as 1987.

By 2008, CRISPR sequences had surfaced in a range of complete bacterial genome sequences and researchers understood their function. They were a defence system that sought out and destroyed viruses.

Viruses of bacteria are called phage, and phage constitute the most abundant biological entity on Earth. Estimates suggest 10 phage exist for each type of bacteria and bacterial cells are more abundant on this planet than stars in the Universe.

Not discovered until 2003, the first giant viruses, mimiviruses rewrote the textbook on what it means ‘to be a virus’ – or not. Mimiviruses are huge. At almost half a micrometre in diameter, they are big enough to be viewed with a light microscope. This is in the size range of bacteria and they were originally misclassified, part of the reason they escaped formal recognition for so long.

The first proof of the existence of mimiviruses came from a sample of amoebae living in a water tower in the UK, which were thought to be ‘just bacteria’, and so stuffed away for safe-keeping. Once retrieved by microbe-hunter Didier Raoult, they were found to be the first representatives of a family of giant viruses that attack amoeba.

Giant viruses are some of the most intriguing and mysterious biological entities left to explore in the natural world. They blur the line between living and non-living. Viruses are non-living because they need a host genome to replicate; living organisms are defined by their ability to self-replicate.

Giant viruses look enough like viruses to be classified as distantly related to a group of viruses that includes smallpox. Yet, they do far more than traditional viruses with their large repertoires of genes, like create their own amino acids. Mimiviruses hold record numbers of novel genes. The metabolisms and activities of these biological entities remain largely unexplored and unknown.

It’s a dog eat dog world. While giant viruses attack amoebas, they in turn are attacked by virophages, further evidence that giant viruses are ‘alive’.

In 2014, the discoverer of the Mimiviruses, virophage and giant virus champion, Didier Raoult and his colleagues found the Zamilon virophage. It selectively infects some mimiviruses but is harmless to others. This discrepancy led Raoult to speculate that mimiviruses harboured a defence system. He modelled his concept on the ‘immune-system’ defences of bacteria.

Raoult sequenced 59 mimivirus strains searching for telltale Zamilon DNA. He searched for the signature pattern of a defence system like CRISPR. CRISPR-CAS systems comprise a set of ‘adopted’ phage sequences that are ‘remembered’ after an infection and an enzyme that can chop up those sequences if the same phage invades again. The more phage attack a bacterium, the more ‘mimic sequences’ it will store up in its library of ‘foreign DNAs to attack’.

Mimviruses use the same strategy. Raoult found snippets of Zamilon sequences in ‘protected’ strains. Adjacent to these sequences lurked an enzyme able to unwind and degrade DNA, the smoking gun.

Destroying parts of this CRISPR-CAS-like system made mimivirus strains vulnerable to Zamilon infection again.

The next step after identifying what Raoult calls the ‘MIMIVIRE’ system is to figure out exactly how it protects the giant virus genome by stopping virophage infections.

Raoult has gone as far as to suggest that giant viruses are not actually viruses at all, but a fourth domain of life. While his argument is contentious, he suggests that this ‘MIMIVIRE’ system supports his theory. He believes giant viruses belong on their own, ancient branch of the Tree of Life.

Just as we need an extra day every four years to keep our calendars in working order, what else might we discover before we understand the reality of the biological diversity found in nature?

The study of giant viruses, and the discovery that they too possess a gene-editing system, offers a gentle reminder of how important the “rare” can be – an especially satisfying scientific way to celebrate Leap Day 2016.

Featured image credit: Bacteria, by geralt. CC0 public domain via Pixabay.