The biggest virus you’ve never heard of (post 2 of 2)

For those of you who read and remember my last blog post you will be familiar with the gigantic mimivirus. Mimivirus was discovered as a virus and not a bacterium back in 2003 by a team who subsequently went on to find a very closely related virus which they termed mamavirus owing to the fact that it is slightly larger than mimi. Once again the sheer size of this virus was somewhat astounding and more importantly the fact that a second giant was found makes it seem more likely that there may be more. But what was really interesting about mamavirus is that when it was first isolated it was done so with another virus in tow.

Sputnik inside mamavirus - from origional Nature paper on Sputnik

Mamavirus is roughly the same size as mimivirus, around 750nm in diameter as I described in the previous blog. However, a virus of much more classical size at 50nm was also seen under the electron microscope. This virus was named Sputnik in honour of the first man-made satellite as it was seen to be a satellite to the much larger mamavirus. Satellite viruses are not a new phenomenon, others have been observed, and at first Sputnik was thought to simply behave like the other satellite viruses in that it would infect its host (in this case an amoeba) at the same time as the larger virus and replicate itself in the host with help from the other virus. However, this was shown not to be the case - Sputnik actually infects mamavirus!

 When mamavirus infects its amoeba host it sets up “viral factories” in the cell where it can replicate its genetic material and make many new copies of itself; the term factory is highly fitting for this process as hundreds upon thousands of new viruses are turned out from these factories, allowing spread of the virus. After it was observed that Sputnik could only grow in the amoeba when mamavirus was simultaneously present, it was seen that the smaller virus actually hijacks these viral factories and uses them for its own replication, to the detriment of mamavirus. Mamavirus as a result becomes unable to replicate itself efficiently and, for want of a better term, becomes sick. Owing to its parasitic actions on mamavirus, Sputnik was coined a virophage (or virus eater).

Before Sputnik, no virus had ever been seen to directly cause damage to another virus, yet a virus infecting a bacterium is not a new idea and was first observed as early as 1915 and 1917, in independent works. These viruses that infect bacteria are known as bacteriophage, hence the logic behind the naming of virophage. I bring bacteria into the story, as one of the exciting aspects of mimi and mama is that they have begun to blur the lines between living organisms and the viruses (again refer back to the previous post). The discovery of smaller viruses that can infect these large viruses further emphasises the idea that they may be on the very cusp of being classed as alive.

Now for something exciting regarding virophage on a somewhat more practical level. I’m sure most people are well aware of the current problem we face with regard to bacterial infections. Back in 1928 when Alexander Fleming somewhat fortuitously discovered penicillin, he launched what has become commonly known as our arms race with bacteria. We are constantly producing antibiotics to limit the burden of infection from bacteria. Yet the bacteria don’t just sit back and let us kill them; they themselves are constantly looking to survive and grow, and as a result they develop protection against our interventions. We develop new antibiotics, the bacteria develop new protections and so on. This evolutionary back and forth can often lead to a steady state where neither has the advantage over the other, which has been termed the Red Queen hypothesis, after the Red Queen in Alice in Wonderland (“It takes all the running you can do to stay in one place…”). However at the present time bacteria seem to have a slight edge over us in this arms race with strains such as MRSA and multidrug resistant tuberculosis becoming ever more common, and the development of new antibiotics slowing down. As a result there is much work being done in the field to find novel prevention strategies against bacterial infection. One area that is being looked into is the potential use of bacteriophage viruses to kill the bacteria. The key to any drug is specificity as this is what makes it safe and limits the side effects, so a virus which only infects bacteria is a promising area to be looking into for ways to target bacterial infection.

Now to move away from bacteria and back to viruses. If bacteriophage can someday be used as an intervention against bacterial infection, then what is to stop us going one step further and using virophage to stop viral infection? What is to stop us from potentially producing a virophage capable of infecting HIV or influenza or any other virus you care to think of? Being that virophage are still a fairly new concept with only three known of (Sputnik, Mavirus and Organic Lake virus) the prospect of producing one capable of targeting specific viruses is some way off yet and to my knowledge not something that is being actively looked at, the current work being merely of the search for new virophage and understanding how they work. However every big idea needs the ground work of discovery and understanding in order to allow manipulation to our own ends. So perhaps in the future, instead of going to the doctors to get a drug prescription, you may head off to the doctors to get a virus. A crazy thought and something that may not be possible but nonetheless fun to think about. Much of science often starts with seemingly crazy thoughts…

The biggest virus you've never heard of (post 1 of 2)

Biology loves to categorise and classify and to that end life on our planet neatly falls into 3 distinct groups: Eukaryotes (us and all life we see around us), bacteria and archaea. However, somewhere between these 3 domains of life and everything else on the planet classed as non-living sit viruses. Ask any scientist if a virus is living or non-living and you will likely get a lot of umming and ahhing and nowhere near a simple answer. The wonderful thing about viruses is that they can only be described within a certain context. When floating around in the environment, viruses are completely inert, no different from a piece of dirt or dust. There is nothing to indicate that they are alive; no growth, no energy consumption, and no chemical activity whatsoever. However as soon as a virus reaches a specific living cell it bursts into ‘life’, becoming highly active and taking over the machinery of the cell to multiply itself many times over. The general definition of a virus is as an obligate intracellular parasite, meaning it needs to be inside a cell to function and will, as a result of this, cause damage to its host. Viruses aren’t the sort of people you’d want at a dinner party as they’d eat all the food you cook, all the food in the kitchen and then trash the house just for good measure, before smashing the windows to leave instead of using the door. While viruses have long been thought of as an entity unto themselves who lurk over all 3 domains of life like a heavy rain cloud, this view is starting to shift. In this blog I’d like to discuss a couple of viruses that are completely changing the classical view of viruses and blurring the boundaries between viruses and the other domains of life.

Back in 1992 an outbreak of pneumonia hit Bradford (UK) and the investigation into the causes led researchers to discover what they thought was a new strain of the Legionella bacteria which they isolated from an amoeba found in a cooling tower. To the team who made this discovery it seemed perfectly reasonable to assume that what they had discovered was a bacterium; it was huge and took up a classic marker stain for bacteria known as the Gram stain. However over a decade later a new team looked at this supposed bacterium and using new high powered microscopes discovered that it was in fact a virus, which they termed “mimivirus” in honour of its ability to mimic a bacterium. The first team weren’t stupid, this virus looks nothing like any other virus known of at the time; for one, it is huge (comparatively). To give some sense of scale: a pin head is usually around 2mm in diameter, a typical red blood cell has a diameter of about 8 micrometres (that’s 0.008mm) and a typical bacterium is about 1 micrometre (0.001mm or 2000 times smaller than a pin head). Getting even smaller, the typical virus is a mere 75 nanometres (that’s a miniscule 0.000075mm). So an average bacterium is around 1000 nanometres and a typical virus is about 75 nanometres;mimivirus is in the region of 600-750 nanometres, a giant amongst viruses and even bigger than a number of bacteria. Hopefully I haven’t lost you with all the numbers but the bottom line is that mimivirus is around 10 times larger than other viruses; imagine bumping into a man who’s 51 feet tall!

EM image of mimivirus

As if the sheer size of this new virus isn’t enough, the tale of mimivirus gets even more interesting. Shortly after it was found to be a virus, people started to look at its genetic material, and what they found shocked the virology community. Viruses always need to infect a host since they are incapable of making proteins or energy (metabolism) for themselves, as they lack any genes that allow them to achieve this. The abilities of metabolism and protein synthesis are thought of as hallmarks of life and are part of the argument against viruses being alive. The thing about mimivirus is that it has many genes needed for both of these processes, meaning that mimivirus is nearly capable of ‘living’ independently of a host. This is a tantalising prospect, as having the ability to replicate and consume energy independently is something only living organisms can do, so the lines between the 3 domains of life and viruses are beginning to blur.

But what does this mean? It is proposed by some that mimivirus may have had an evolutionary ancestor that was even more independent that it is now, potentially to the extent of not needing a host and therefore not being a virus by our definition. It is claimed that over time this virus became more dependent on a host and lost some of its abilities, leaving us with the virus we see today. However nothing in science is straight forward and some argue against this ‘regression model’ of evolution and instead assert that mimivirus has acquired these complex genes from other organisms, some stolen from the amoeba they infect and others from bacteria that can simultaneously infect the amoeba. 

I don’t intend to pick sides in the debate over the origin of the genes, however let us pretend that the argument for regression evolution turns out to be the case, as this would have some very big implications that are fun to think about. Some of the genes mimi has are seen to be conserved among viruses that infect all 3 domains of life. When a relationship like this is seen in evolution it usually means that somewhere in the distant past there was a shared ancestor. To use Darwin’s brilliant tree of life metaphor for evolution, it is possible that a close ancestor of mimi may be the one which sat at the very base of the virus tree and therefore gave rise to all other viruses. This argument isn’t perfect since the question can be raised as to why mimivirus has stayed so close to the ancestral virus when other viruses have moved away so much, but an exciting idea nonetheless.

Darwin's sketch of the tree of life

However, some go even further and argue that the mimi ancestor may also have been the seed that started the Eukaryotic tree to which we belong. I have previously written a blog regarding the evolution of Eukaryotic cells, but that blog was looking at the endosymbitoic theory and the ability of cells to produce energy, it did not look at the nucleus. The nucleus is often referred to as the brain or the control centre of the cell as it houses the DNA which has the potential to control the cell. The nucleus is what separates complex, Eukaryotic life from the simple bacterial and archael life and its origin is a contentious issue. It is proposed by some that a mimi-like virus may be the origin of the nucleus. Like us mimivirus has a DNA genome so it is possible that a mimivirus ancestor could have entered a simple cell and instead of damaging and destroying it, could have instead set up residence in its host and entered a symbiotic relationship instead of a pathogenic one, given the birth of nucleated life which, billions of years later, would give us the world we see around us.

Who would have thought back in 1992 that an outbreak of pneumonia in Bradford would lead to the discovery of a virus with the potential not only to change many fundamental concepts of virology but also to shine a light on the birth of complex life? As if that isn’t enough, a very similar virus to mimivirus was also discovered termed mamavirus which has given rise to a completely novel concept of viruses, the virophage which I will discuss in my next blog. So come back soon.

It's been a while

It's been a pretty long time since I wrote a blog post due to Christmas and a stupidly busy January. However there is a new post in the works and after that the postings will become more regular again.  So keep checking back to have a read - updates will be posted on Twitter